CAR-T celtherapie (voluit geschreven als Chimeric Antigen Receptor T-Cel therapie) is een vorm van gepersonaliseerde immuuntherapie die vooral bij vormen van leukemie en lymfklierkanker succesvol en goedgekeurd zijn. Maar ook bij solide tumoren wordt vooruitgang geboekt. In 2017 publiceerde JAMA een overzicht (zie onderaan abstract) en juli 2025 werd opnieuw een overzicht en stand van zaken gepubliceerd. 

Uit dat laatste overzicht heb ik wat belangrijke citaten vertaald in het Nederlands vertaalt met extra aandacht voor CAR-T celtherapie bij  Acute Myeloide Leukemie - AML.

Als eerste een introductie op deze stand van zaken:

CAR-T celtherapie heeft de behandeling van een recidief en niet op medicijnen reagerende Lymfoom B-cel kanker en multiple myeloma veranderd door geactiveerde T-cellen te herleiden naar een CD19 mutatie of naar BCMA-expressieve tumorcellen. Deze aanpak is echter nog niet goedgekeurd voor Acute Myeloide Leukemie - AML, de meest voorkomende vorm van leukemie bij volwassenen en ouderen. Tegelijkertijd blijven CAR-T celtherapiën aanzienlijke uitdagingen ondervinden bij de behandeling van solide tumoren.

Deze review begint met een uitgebreid overzicht van CAR-T celtherapie voor kanker in het algemeen, met aandacht voor de structuur van CAR-T-cellen en de geschiedenis van hun klinische toepassing. Vervolgens wordt het huidige landschap van CAR-T celtherapie bij zowel hematologische maligniteiten als solide tumoren onderzocht. Tot slot gaat de review in op de specifieke uitdagingen bij de toepassing van CAR-T celtherapie bij Acute Myeloide Leukemie - AML, belicht lopende wereldwijde klinische studies en schetst mogelijke toekomstige richtingen voor de ontwikkeling van effectieve CAR-T-celgebaseerde behandelingen voor recidiverende/refractaire Acute Myeloide Leukemie - AML.

Een korte beschrijving van wat CAR-T cellen precies zijn:

CAR-T-celstructuur:

CAR-T cellen zijn geconstrueerde receptoren die bestaan ​​uit een combinatie van een endodomein, een verankerend transmembraandomein en een ectodomein.(Ref. 26,27). Dit laatste is een ligandspecifiek extracellulair domein dat bestaat uit een enkelketenig variabel fragment (scFv) en een scharnier. (Ref. 28). 
Het scFv is een fusie-eiwit van de variabele regio's van de lichte en zware ketens van immunoglobulinen, verbonden door een korte flexibele peptidelinker. (Ref. 29).
Het scharnier, ook wel spacer genoemd, scheidt de bindingseenheden van het transmembraandomein. (Ref. 30). De meeste CAR-T-cellen zijn ontworpen met immunoglobuline-achtige domeinscharnieren, die flexibiliteit bieden bij de toegang tot het doelantigeen. (Ref. 31,32).
Het endodomein kan bestaan ​​uit het intracellulaire T-celactiveringsdomein van CD37, als een enkele entiteit of uit een of meer intracellulaire co-stimulerende (of activerende) domeinen. (Ref. 33).
Hoewel het scFv antigeen specificiteit biedt, zijn de co-stimulerende domeinen essentieel voor de activering van effector T cellen. (Ref. 34). 
CAR-T-cellen worden ingedeeld in vijf generaties op basis van het endodomein (Figuur. 1). (Ref. 35,36,37).

Zie deze grafische afbeelding van bovenstaande tekst:



Structure of CARs. First-generation CARs consist of a ligand or scFv ectodomain and a CD3ζ TCR-type intracellular signal. Second-generation CARs contain a scFv extracellular domain and a co-stimulatory domain, 4-1BB or CD28. Third-generation CARs contain two co-stimulatory domains (usually 4-1BB and CD28). Fourth-generation CARs (TRUCKs) contain a domain encoding a specific cytokine or signal blocker/inducer. Fifth-generation CARs contain three synergistic co-stimulatory signals. This figure was created using Biorender.com

Een volgende citaat gaat over de toepassing bij kanker in het algemeen:

CAR-T-cel bij kanker: huidige situatie

Geschiedenis van de implementatie van CAR-T-cellen

Moderne CAR-T celtherapie is het resultaat van tientallen jaren baanbrekend onderzoek naar immunologie en genetische manipulatie. Hier geven we een kort overzicht van de belangrijkste bijdragen die de weg hebben vrijgemaakt voor de eerste goedkeuringen en het daaropvolgende gebruik bij duizenden patiënten wereldwijd. (Figuur. 2).



The timeline of milestones in CAR-T cell development. The first reports published in scientific journals or conference abstracts, excluding patent applications, are highlighted. The efficacy of CD19 CAR-T cells was reported in patients with B-NHL in 2010, CLL in 2011, and B-ALL in 2013. The figure was created using Biorender.com

We maken een stap verder in het studierapport en komen op de tot nu toe geregistreerde en goedgekeurde vormen van CAR-T cel behandelingen:

CAR-T-therapieën voor hematologische maligniteiten en solide tumoren: huidige scenario 

De Amerikaanse Food and Drug Administration (FDA) heeft zes CAR-T-celtherapieën goedgekeurd voor de behandeling van verschillende hematologische maligniteiten. Kymriah®, een tweedegeneratie CAR-T-celtherapie gericht op het B-celantigeen CD19, was de eerste CAR-T-celtherapie die door de FDA en het Europees Geneesmiddelenbureau (EMA) werd goedgekeurd voor de behandeling van kinderen en jongvolwassenen met ALL - Acute Lymfatische Leukemie. (Ref. 109,111,112 )

De FDA en EMA hebben vervolgens drie aanvullende CAR-T-celtherapieën goedgekeurd die gericht zijn op het CD19-antigeen: Yescarta®,(Ref. 113,114,115) Tecartus®, (Ref. 65,113) en lisocabtagene maraleucel (Breyanzi®).(Ref. 116,117) Daarnaast zijn twee B-celmaturatie-antigeen (BCMA) CAR-T-celproducten goedgekeurd voor de behandeling van R/R MM, idecabtagene vicleucel (Abecma®),(Ref. 113,114,115) Tecartus®, (Ref. 65,113) idecabtagene vicleucel (Abecma®) (Ref. 118) in Maart 2021 en Carvykti® in Februari 2022. (Ref. 66,119,120) 
Momenteel lopen er verschillende klinische onderzoeken waarin deze zes CAR-T-cellen worden getest voor verdere indicaties (Table 1).(Ref. 113,114,115 Tecartus®, (Ref. 65,113 en lisocabtagene maraleucel (Breyanzi®). (Ref. 116,117).

CAR-T-therapie is een baanbrekende behandeling voor hematologische kankers, maar de effectiviteit ervan bij kanker met solide tumoren is beperkt gebleven. Tot op heden heeft geen enkele CAR-T-celtherapie FDA- of EMA-goedkeuring gekregen voor solide tumoren (Tafel 1), wat de dringende noodzaak van vooruitgang in deze context onderstreept. Verschillende factoren kunnen bijdragen aan de beperkte effectiviteit van CAR-T-cellen bij solide tumoren, zoals de antigene heterogeniteit en de tumormicro-omgeving (TME). De TME wordt gekenmerkt door een sterke immuunonderdrukkende, hypoxische en fibrotische werking, waardoor een fysieke en biologische barrière ontstaat die verhindert dat CAR-T-cellen de tumorcellen bereiken. Bovendien hebben verschillende studies een beperkte expansie en een kortere aanwezigheid van CAR-T-cellen aangetoond bij patiënten met solide tumoren. (ref. 121,122,123).

Tot slot een overzicht van CAR-T celtherapie bij Acute Myeloide Leukemie - AML:

Uitdagingen geassocieerd met CAR-T cellen bij Acute Myeloide Leukemie - AML.

De ervaring met de behandeling van een recidief of falende behandelingen bij patiënten met Lymfoom B-cel kanker en een recidief of falende behandelingen bij multiple myeloma met CAR-T-celtherapie heeft verschillende kenmerken aan het licht gebracht die veelbelovende resultaten opleveren. Deze omvatten onder andere de moleculaire structuur en co-stimulerende domeinen van CAR, het beoogde antigeen, de transductiemethode, het lymfodepletieregime voorafgaand aan celinfusie, de geïnfundeerde celdoses, de heterogeniteit van de patiëntenpopulatie en de intrinsieke kenmerken van de tumorcellen.

De belangrijkste uitdagingen in de AML-setting zijn drieledig:

1. i) de klonale heterogeniteit van de ziekte,
2. ii) de sterk immunosuppressieve micro-omgeving van het beenmerg (BM), en
3. iii) het gebrek aan tumorspecifieke doelwitantigenen (Figuur 3). (Ref. 22,133,134)

Heterogeniteit van AML

Tegenwoordig is  Acute Myeloide Leukemie - AML een brede categorie die verschillende ziekten omvat, elk met verschillende moleculaire en cytogenetische afwijkingen. (Ref. 135,136,137) Deze moleculaire en cytogenetische heterogeniteit wordt weerspiegeld in de huidige diagnostische realiteit, waar drie belangrijke internationale classificaties bestaan: de WHO 2022,(Ref. 138) die 11 AML-groepen definieert op basis van genetische afwijkingen; de ELN 2022, (Ref. 139) die gebaseerd is op de vorige, maar 14 AML-groepen identificeert en zich richt op prognose en behandeling; en de ICC 2022, (Ref. 140) die 18 entiteiten erkent. Hoewel er in de loop van de tijd nieuwe, naar risico gestratificeerde moleculaire subgroepen van AML kunnen ontstaan, correleren niet alle genexpressiesubtypen goed met ziektegerelateerde genfusies of mutaties. (Ref. 141)

Deze heterogeniteit ontstaat door meerdere factoren die de presentatie, progressie en respons op behandeling van de ziekte beïnvloeden. AML wordt gekenmerkt door een diverse reeks genetische mutaties die belangrijke paden beïnvloeden, waaronder signaaltransductie (FLT3), epigenetische regulatie (DNMT3A, IDH1/2, EZH2) en apoptose (TP53). (Ref. 4) Deze mutaties sturen verschillende transcriptionele programma's aan en dragen bij aan de variabiliteit in ziektegedrag en medicijngevoeligheid.142 
Bovendien beïnvloeden chromosomale translocaties (bijv. t(8;21), inv(16), t(15;17)) de prognose en behandelstrategieën van AML verder. Een andere complexiteitslaag komt voort uit de klonale evolutie van AML, waarbij subklonen met verschillende genetische profielen bijdragen aan intratumorale heterogeniteit.(Ref. 143) Deze moleculaire en cytogenetische veranderingen vormen de basis voor prognostische classificaties, aangezien ze cruciale factoren zijn die de behandelresultaten en overleving beïnvloeden. AML met een complex of monosomaal karyotype, structurele afwijkingen met betrekking tot chromosoom 3, TP53-mutaties, FLT3-mutaties met een hoge allelische ratio, of mutaties in ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1 en ZRSR2 (geclassificeerd als AML met myelodysplasiegerelateerde genmutaties)(Ref. 140)  worden bijvoorbeeld geassocieerd met behandelingsresistentie en recidief, waardoor het in de ELN 2022-groep met een ongunstige prognose valt.(Ref. 139).

Lees verder over CAR-T cel behandelingen bij Acute Myeloide Leukemie - AML in het studierapport dat zeer gedetailleerd de verschillende opties beschrijft inclusief lopende studies.

Eerst het studierapport uit 2017. Daaronder het studierapport uit juli 2025 met referentielijst

CAR-T cell therapy for cancer: current challenges and future directions. Including for Acute Myeloide Leukemia

References

1. Kochenderfer, J. N. et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 119, 2709–2720 (2012).

   Article CAS PubMed PubMed Central Google Scholar 

2. Porter, D. L. et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl. Med. 7, 303ra139 (2015).

   Article PubMed PubMed Central Google Scholar 

3. University of Pennsylvania. University of Pennsylvania and Novartis Form Alliance to Expand Use of Personalized T Cell Therapy for Cancer Patients. University of Pennsylvania and Penn Medicine announce breakthrough in the treatment of a rare genetic disease. Penn Medicine https://www.pennmedicine.org/news/news-releases/2012/august/university-of-pennsylvania-and (2012).

4. Costandi, M. Kite and NCI partner on T cells. Nat. Biotechnol. 31, 10–10 (2013).

   Article Google Scholar 

5. Memorial Sloan Kettering Cancer Center. New biotech startup will pit immune system against cancer with cutting-edge gene therapy. Memorial Sloan Kettering Cancer Center https://www.mskcc.org/news/new-biotech-startup-will-pit-immune-system-against (2020).

6. Braendstrup, P., Levine, B. L. & Ruella, M. The long road to the first FDA-approved gene therapy: chimeric antigen receptor T cells targeting CD19. Cytotherapy 22, 57–69 (2020).

   Article CAS PubMed PubMed Central Google Scholar 

7. Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).

   Article CAS PubMed PubMed Central Google Scholar 

8. Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017).

   Article CAS PubMed PubMed Central Google Scholar 

9. Fowler, N. H. et al. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat. Med. 28, 325–332 (2022).

   Article CAS PubMed Google Scholar 

10. Schuster, S. J. et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N. Engl. J. Med. 380, 45–56 (2019).

    Article CAS PubMed Google Scholar 

11. Locke, F. L. et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol. 20, 31–42 (2019).

    Article CAS PubMed Google Scholar 

12. Frey, N. V. Approval of brexucabtagene autoleucel for adults with relapsed and refractory acute lymphocytic leukemia. Blood 140, 11–15 (2022).

    Article CAS PubMed Google Scholar 

13. Bouchkouj, N. et al. FDA approval summary: brexucabtagene autoleucel for treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Oncologist 27, 892–899 (2022).

    Article PubMed PubMed Central Google Scholar 

14. Sehgal, A. R. et al. Lisocabtagene maraleucel (liso-cel) for treatment of second-line (2L) transplant noneligible (TNE) relapsed/refractory (R/R) aggressive large B-cell non-Hodgkin lymphoma (NHL): Updated results from the PILOT study. J. Clin. Oncol. 38, 8040–8040 (2020).

    Article Google Scholar 

15. Abramson, J. S. et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet 396, 839–852 (2020).

    Article PubMed Google Scholar 

16. Munshi, N. C. et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N. Engl. J. Med. 384, 705–716 (2021).

    Article CAS PubMed Google Scholar 

17. Chekol Abebe, E., Yibeltal Shiferaw, M., Tadele Admasu, F. & Asmamaw Dejenie, T. Ciltacabtagene autoleucel: the second anti-BCMA CAR T-cell therapeutic armamentarium of relapsed or refractory multiple myeloma. Front. Immunol. 13, 1007515 (2022).

18. Martin, T. et al. Ciltacabtagene autoleucel, an anti–B-cell maturation antigen chimeric antigen receptor T-cell therapy, for relapsed/refractory multiple myeloma: CARTITUDE-1 2-year follow-up. J. Clin. Oncol. 41, 1265–1274 (2022).

    Article PubMed PubMed Central Google Scholar 

19. Narayan, V. et al. PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat. Med. 28, 724–734 (2022).

    Article CAS PubMed PubMed Central Google Scholar 

20. Haas, A. R. et al. Phase I study of lentiviral-transduced chimeric antigen receptor-modified T cells recognizing mesothelin in advanced solid cancers. Mol. Ther. 27, 1919–1929 (2019).

    Article CAS PubMed PubMed Central Google Scholar 

21. O’Rourke, D. M. et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci. Transl. Med. 9, eaag3518 (2017).

22. Brown, C. E. et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N. Engl. J. Med. 375, 2561–2569 (2016).

    Article CAS PubMed PubMed Central Google Scholar 

23. Majzner, R. G. et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022).

    Article CAS PubMed PubMed Central Google Scholar 

24. Qi, C. et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat. Med. 28, 1189–1198 (2022).

    Article CAS PubMed PubMed Central Google Scholar 

25. Del Bufalo, F. et al. GD2-CART01 for relapsed or refractory high-risk neuroblastoma. N. Engl. J. Med. 388, 1284–1295 (2023).

    Article PubMed Google Scholar 

26. Brudno, J. N., Maus, M. V. & Hinrichs, C. S. CAR T-cells and T-cell therapies for cancer: a translational science review. JAMA 332, 1924–1935 (2024).

    Article CAS PubMed PubMed Central Google Scholar 

27. D’Angelo, S. P. et al. Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial. Lancet 403, 1460–1471 (2024).

    Article PubMed PubMed Central Google Scholar 

28. Norberg, S. M. & Hinrichs, C. S. Engineered T cell therapy for viral and non-viral epithelial cancers. Cancer Cell 41, 58–69 (2023).

    Article CAS PubMed Google Scholar 

29. Nagarsheth, N. B. et al. TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nat. Med. 27, 419–425 (2021).

    Article CAS PubMed PubMed Central Google Scholar 

30. Doran, S. L. et al. T-cell receptor gene therapy for human papillomavirus–associated epithelial cancers: a first-in-human, phase I/II study. J. Clin. Oncol. 37, 2759–2768 (2019).

    Article CAS PubMed PubMed Central Google Scholar 

31. Diaz de la Guardia, R. et al. Detailed characterization of mesenchymal stem/stromal cells from a large cohort of aml patients demonstrates a definitive link to treatment outcomes. Stem Cell Rep. 8, 1573–1586 (2017).

    Article CAS Google Scholar 

32. Vanhooren, J. et al. CAR-T in the treatment of acute myeloid leukemia: barriers and how to overcome them. Hemasphere 7, e937 (2023).

    Article CAS PubMed PubMed Central Google Scholar 

33. Estey, E. & Döhner, H. Acute myeloid leukaemia. Lancet 368, 1894–1907 (2006).

    Article PubMed Google Scholar 

34. Padmakumar, D. et al. A concise review on the molecular genetics of acute myeloid leukemia. Leuk. Res 111, 106727 (2021).

    Article CAS PubMed Google Scholar 

35. Ediriwickrema, A., Gentles, A. J. & Majeti, R. Single-cell genomics in AML: extending the frontiers of AML research. Blood 141, 345–355 (2023).

    Article CAS PubMed Google Scholar 

36. Khoury, J. D. et al. The 5th edition of the world health organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia 36, 1703–1719 (2022).

    Article PubMed PubMed Central Google Scholar 

37. Döhner, H. et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 140, 1345–1377 (2022).

    Article PubMed Google Scholar 

38. Arber, D. A. et al. International consensus classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood 140, 1200–1228 (2022).

    Article CAS PubMed PubMed Central Google Scholar 

39. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059–2074 (2013).

40. Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3, 730–737 (1997).

    Article CAS PubMed Google Scholar 

41. Gentles, A. J. Association of a leukemic stem cell gene expression signature with clinical outcomes in acute myeloid leukemia. JAMA 304, 2706 (2010).

    Article CAS PubMed PubMed Central Google Scholar 

42. Thomas, D. & Majeti, R. Biology and relevance of human acute myeloid leukemia stem cells. Blood 129, 1577–1585 (2017).

    Article CAS PubMed PubMed Central Google Scholar 

43. Morita, K. et al. Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics. Nat. Commun. 11, 5327 (2020).

    Article CAS PubMed PubMed Central Google Scholar 

44. Eppert, K. et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat. Med. 17, 1086–1093 (2011).

    Article CAS PubMed Google Scholar 

45. Jiang, L. et al. Multidimensional study of the heterogeneity of leukemia cells in t(8;21) acute myelogenous leukemia identifies the subtype with poor outcome. Proc. Natl. Acad. Sci. USA117, 20117–20126 (2020).

    Article CAS PubMed PubMed Central Google Scholar 

46. Paczulla, A. M. et al. Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion. Nature 572, 254–259 (2019).

    Article CAS PubMed PubMed Central Google Scholar 

47. Rickmann, M. et al. Elevated frequencies of leukemic myeloid and plasmacytoid dendritic cells in acute myeloid leukemia with the FLT3 internal tandem duplication. Ann. Hematol. 90, 1047–1058 (2011).

    Article CAS PubMed PubMed Central Google Scholar 

48. Chen, J.-Y. et al. The oncometabolite R-2-hydroxyglutarate activates NF-κB-dependent tumor-promoting stromal niche for acute myeloid leukemia cells. Sci. Rep. 6, 32428 (2016).

    Article CAS PubMed PubMed Central Google Scholar 

49. Sasaki, M. et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488, 656–659 (2012).

    Article CAS PubMed PubMed Central Google Scholar 

50. Brummer, T. & Zeiser, R. The role of the MDM2/p53 axis in antitumor immune responses. Blood 143, 2701–2709 (2024).

    Article CAS PubMed Google Scholar 

51. Daver, N. G. et al. TP53-mutated myelodysplastic syndrome and acute myeloid leukemia: biology, current therapy, and future directions. Cancer Discov. 12, 2516–2529 (2022).

    Article CAS PubMed PubMed Central Google Scholar 

52. Voskarides, K. & Giannopoulou, N. The role of TP53 in adaptation and evolution. Cells 12, 512 (2023).

    Article CAS PubMed PubMed Central Google Scholar 

53. McCurdy, S. R. et al. Loss of the mismatched human leukocyte antigen haplotype in two acute myelogenous leukemia relapses after haploidentical bone marrow transplantation with post-transplantation cyclophosphamide. Leukemia 30, 2102–2106 (2016).

    Article CAS PubMed PubMed Central Google Scholar 

54. Crucitti, L. et al. Incidence, risk factors and clinical outcome of leukemia relapses with loss of the mismatched HLA after partially incompatible hematopoietic stem cell transplantation. Leukemia 29, 1143–1152 (2015).

    Article CAS PubMed Google Scholar 

55. Vago, L. et al. Loss of mismatched HLA in Leukemia after stem-cell transplantation. N. Engl. J. Med. 361, 478–488 (2009).

    Article CAS PubMed Google Scholar 

56. Binder, S., Luciano, M. & Horejs-Hoeck, J. The cytokine network in acute myeloid leukemia (AML): a focus on pro- and anti-inflammatory mediators. Cytokine Growth Factor Rev. 43, 8–15 (2018).

    Article CAS PubMed Google Scholar 

57. Wu, Y., Chen, P., Huang, H.-F., Huang, M.-J. & Chen, Y.-Z. Reduction of transforming growth factor-β1 expression in leukemia and its possible role in leukemia development. Leuk. Lymphoma 53, 145–151 (2012).

    Article CAS PubMed Google Scholar 

58. Bhagwat, A. S. et al. Cytokine-mediated CAR T therapy resistance in AML. Nat. Med. 30, 3697–3708 (2024).

    Article CAS PubMed PubMed Central Google Scholar 

59. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    Article Google Scholar 

60. Mussai, F. et al. Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment. Blood 122, 749–758 (2013).

    Article CAS PubMed PubMed Central Google Scholar 

61. Tettamanti, S., Pievani, A., Biondi, A., Dotti, G. & Serafini, M. Catch me if you can: how AML and its niche escape immunotherapy. Leukemia 36, 13–22 (2022).

    Article PubMed Google Scholar 

62. Mishra, S. K., Millman, S. E. & Zhang, L. Metabolism in acute myeloid leukemia: mechanistic insights and therapeutic targets. Blood 141, 1119–1135 (2023).

    Article CAS PubMed Google Scholar 

63. van Vlerken-Ysla, L., Tyurina, Y. Y., Kagan, V. E. & Gabrilovich, D. I. Functional states of myeloid cells in cancer. Cancer Cell 41, 490–504 (2023).

    Article PubMed PubMed Central Google Scholar 

64. Gabrilovich, D. I. Myeloid-derived suppressor cells. Cancer Immunol. Res. 5, 3–8 (2017).

    Article CAS PubMed PubMed Central Google Scholar 

65. Veglia, F., Sanseviero, E. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat. Rev. Immunol. 21, 485–498 (2021).

    Article CAS PubMed PubMed Central Google Scholar 

66. Guo, M. et al. Core binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis. Blood https://doi.org/10.1182/blood.2022015830 (2023).

67. Cheng, Y. et al. N6-methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation. Cancer Cell 39, 958–972.e8 (2021).

    Article CAS PubMed PubMed Central Google Scholar 

68. Mabuchi, R. et al. High serum concentration of L-kynurenine predicts unfavorable outcomes in patients with acute myeloid leukemia. Leuk. Lymphoma 57, 92–98 (2016).

    Article CAS PubMed Google Scholar 

69. Ghobrial, I. M., Detappe, A., Anderson, K. C. & Steensma, D. P. The bone-marrow niche in MDS and MGUS: implications for AML and MM. Nat. Rev. Clin. Oncol. 15, 219–233 (2018).

    Article PubMed Google Scholar 

70. Hao, F., Sholy, C., Wang, C., Cao, M. & Kang, X. The role of t cell immunotherapy in acute myeloid leukemia. Cells 10, 3376 (2021).

    Article CAS PubMed PubMed Central Google Scholar 

71. Zhang, Z. et al. Single-cell RNA-seq reveals a microenvironment and an exhaustion state of T/NK cells in acute myeloid leukemia. Cancer Sci. 114, 3873–3883 (2023).

    Article CAS PubMed PubMed Central Google Scholar 

72. Vadakekolathu, J. & Rutella, S. Escape from T-cell–targeting immunotherapies in acute myeloid leukemia. Blood 143, 2689–2700 (2024).

    Article CAS PubMed Google Scholar 

73. Noviello, M. et al. Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT. Nat. Commun. 10, 1065 (2019).

    Article PubMed PubMed Central Google Scholar 

74. Haroun, F., Solola, S. A., Nassereddine, S. & Tabbara, I. PD-1 signaling and inhibition in AML and MDS. Ann. Hematol. 96, 1441–1448 (2017).

    Article CAS PubMed Google Scholar 

75. Abbas, H. A. et al. Single cell T cell landscape and T cell receptor repertoire profiling of AML in context of PD-1 blockade therapy. Nat. Commun. 12, 6071 (2021).

    Article CAS PubMed PubMed Central Google Scholar 

76. Nuebling, T. et al. The immune checkpoint modulator OX40 and its ligand OX40L in NK-cell immunosurveillance and acute myeloid leukemia. Cancer Immunol. Res. 6, 209–221 (2018).

    Article CAS PubMed Google Scholar 

77. Atilla, E. & Benabdellah, K. The black hole: CAR T cell therapy in AML. Cancers15, 2713 (2023).

    Article CAS PubMed PubMed Central Google Scholar 

78. Tikhonova, A. N. et al. The bone marrow microenvironment at single-cell resolution. Nature 569, 222–228 (2019).

    Article CAS PubMed PubMed Central Google Scholar 

79. Finney, O. C. et al. CD19 CAR T cell product and disease attributes predict leukemia remission durability. J. Clin. Investig. 129, 2123–2132 (2019).

    Article PubMed PubMed Central Google Scholar 

80. Labanieh, L. & Mackall, C. L. CAR immune cells: design principles, resistance and the next generation. Nature 614, 635–648 (2023).

    Article CAS PubMed Google Scholar 

81. Krönig, H. et al. Interferon-induced programmed death-ligand 1 (PD-L1/B7-H1) expression increases on human acute myeloid leukemia blast cells during treatment. Eur. J. Haematol. 92, 195–203 (2014).

    Article PubMed Google Scholar 

82. Good, C. R. et al. An NK-like CAR T cell transition in CAR T cell dysfunction. Cell 184, 6081–6100.e26 (2021).

    Article CAS PubMed PubMed Central Google Scholar 

83. Lynn, R. C. et al. c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature 576, 293–300 (2019).

    Article CAS PubMed PubMed Central Google Scholar 

84. Al-Matary, Y. S. et al. Acute myeloid leukemia cells polarize macrophages towards a leukemia supporting state in a Growth factor independence 1 dependent manner. Haematologica 101, 1216–1227 (2016).

    Article CAS PubMed PubMed Central Google Scholar 

85. Toffalori, C. et al. Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation. Nat. Med. 25, 603–611 (2019).

    Article CAS PubMed Google Scholar 

86. Jia, B. et al. Bone marrow CD8 T cells express high frequency of PD-1 and exhibit reduced anti-leukemia response in newly diagnosed AML patients. Blood Cancer J. 8, 34 (2018).

    Article PubMed PubMed Central Google Scholar 

87. Le Dieu, R. et al. Peripheral blood T cells in acute myeloid leukemia (AML) patients at diagnosis have abnormal phenotype and genotype and form defective immune synapses with AML blasts. Blood 114, 3909–3916 (2009).

    Article PubMed PubMed Central Google Scholar 

88. Behl, D. et al. Absolute lymphocyte count recovery after induction chemotherapy predicts superior survival in acute myelogenous leukemia. Leukemia 20, 29–34 (2006).

    Article CAS PubMed Google Scholar 

89. Restelli, C. et al. Recent advances in immune-based therapies for acute myeloid leukemia. Blood Cancer Discov. 5, 234–248 (2024).

    Article CAS PubMed PubMed Central Google Scholar 

90. Baryawno, N. et al. A cellular taxonomy of the bone marrow stroma in homeostasis and leukemia. Cell 177, 1915–1932.e16 (2019).

    Article CAS PubMed PubMed Central Google Scholar 

91. Haubner, S. et al. Cooperative CAR targeting to selectively eliminate AML and minimize escape. Cancer Cell 41, 1871–1891.e6 (2023).

    Article CAS PubMed PubMed Central Google Scholar 

92. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article CAS PubMed PubMed Central Google Scholar 

93. Ritchie, D. S. et al. Persistence and efficacy of second generation CAR T cell against the ley antigen in acute myeloid leukemia. Mol. Ther. 21, 2122–2129 (2013).

    Article CAS PubMed PubMed Central Google Scholar 

94. Majzner, R. G. & Mackall, C. L. Clinical lessons learned from the first leg of the CAR T cell journey. Nat. Med. 25, 1341–1355 (2019).

    Article CAS PubMed Google Scholar 

95. Jordan, C. et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia 14, 1777–1784 (2000).

    Article CAS PubMed Google Scholar 

96. Haubner, S. et al. Coexpression profile of leukemic stem cell markers for combinatorial targeted therapy in AML. Leukemia 33, 64–74 (2019).

    Article CAS PubMed Google Scholar 

97. Schorr, C. & Perna, F. Targets for chimeric antigen receptor T-cell therapy of acute myeloid leukemia. Front. Immunol. 13, 1085978 (2022).

98. Munoz, L. et al. Interleukin-3 receptor alpha chain (CD123) is widely expressed in hematologic malignancies. Haematologica 86, 1261–1269 (2001).

    CAS PubMed Google Scholar 

99. Pelosi, E., Castelli, G. & Testa, U. CD123 a therapeutic target for acute myeloid leukemia and blastic plasmocytoid dendritic neoplasm. Int. J. Mol. Sci. 24, 2718 (2023).

    Article CAS PubMed PubMed Central Google Scholar 

100. Baroni, M. L. et al. 41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo. J. Immunother. Cancer 8, e000845 (2020).

     Article PubMed PubMed Central Google Scholar 

101. Frankel, A. E. et al. Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients. Blood 124, 385–392 (2014).

     Article CAS PubMed PubMed Central Google Scholar 

102. Frankel, A., Liu, J.-S., Rizzieri, D. & Hogge, D. Phase I clinical study of diphtheria toxin-interleukin 3 fusion protein in patients with acute myeloid leukemia and myelodysplasia. Leuk. Lymphoma 49, 543–553 (2008).

     Article CAS PubMed Google Scholar 

103. He, S. Z. et al. A phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti-CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia. Leuk. Lymphoma 56, 1406–1415 (2015).

     Article CAS PubMed Google Scholar 

104. Montesinos, P. et al. Safety and efficacy of talacotuzumab plus decitabine or decitabine alone in patients with acute myeloid leukemia not eligible for chemotherapy: results from a multicenter, randomized, phase 2/3 study. Leukemia 35, 62–74 (2021).

     Article CAS PubMed Google Scholar 

105. Naveen, P. et al. Tagraxofusp in blastic plasmacytoid dendritic-cell neoplasm. N. Engl. J. Med. 380, 1628–1637 (2019).

     Article Google Scholar 

106. Lane, A. A. et al. Safety and efficacy of combining tagraxofusp (SL-401) with azacitidine or azacitidine and venetoclax in a phase 1b study for CD123 positive AML, MDS, or BPDCN. Blood 138, 2346–2346 (2021).

     Article Google Scholar 

107. Daver, N. G. et al. Clinical profile of IMGN632, a novel CD123-targeting antibody-drug conjugate (ADC), in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) or blastic plasmacytoid dendritic cell neoplasm (BPDCN). Blood 134, 734–734 (2019).

     Article Google Scholar 

108. Daver, N. et al. Broad activity for the pivekimab sunirine (PVEK, IMGN632), azacitidine, and venetoclax triplet in high-risk patients with relapsed/refractory acute myeloid leukemia (AML). Blood 140, 145–149 (2022).

     Article Google Scholar 

109. Ravandi, F. et al. Complete responses in relapsed/refractory acute myeloid leukemia (AML) patients on a weekly dosing schedule of vibecotamab (XmAb14045), a CD123 x CD3 T cell-engaging bispecific antibody; initial results of a phase 1 study. Blood 136, 4–5 (2020).

     Article Google Scholar 

110. Godwin, J. E. et al. Flotetuzumab (FLZ), an investigational CD123 x CD3 bispecific dart® protein-induced clustering of CD3+ T cells and CD123+ AML cells in bone marrow biopsies is associated with response to treatment in primary refractory AML patients. Blood 134, 1410 (2019).

     Article Google Scholar 

111. Uy, G. L. et al. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood 137, 751–762 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

112. Winer, E. S. et al. A phase 1, first-in-human, dose-escalation study of MGD024, a CD123 x CD3 bispecific dart® molecule, in patients with relapsed or refractory CD123-positive (+) hematologic malignancies. Blood 140, 11753–11754 (2022).

     Article Google Scholar 

113. Stein, C. et al. Novel conjugates of single-chain Fv antibody fragments specific for stem cell antigen CD123 mediate potent death of acute myeloid leukaemia cells. Br. J. Haematol. 148, 879–889 (2010).

     Article CAS PubMed Google Scholar 

114. Ehninger, A. et al. Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. Blood Cancer J. 4, e218–e218 (2014).

     Article CAS PubMed PubMed Central Google Scholar 

115. Dinndorf, P. et al. Expression of normal myeloid-associated antigens by acute leukemia cells. Blood 67, 1048–1053 (1986).

     Article CAS PubMed Google Scholar 

116. Walter, R. B., Appelbaum, F. R., Estey, E. H. & Bernstein, I. D. Acute myeloid leukemia stem cells and CD33-targeted immunotherapy. Blood 119, 6198–6208 (2012).

     Article CAS PubMed PubMed Central Google Scholar 

117. Castaigne, S. et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet 379, 1508–1516 (2012).

     Article CAS PubMed Google Scholar 

118. Burnett, A. K. et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J. Clin. Oncol. 29, 369–377 (2011).

     Article CAS PubMed Google Scholar 

119. FDA. MYLOTARGTM (Gemtuzumab Ozogamicin) for Injection. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761060lbl.pdf (accessed on 1 Sep 2024).

120. EMA. EPAR—Summary for Mylotarg—Epar Product Information Public. Available online: https://www.ema.europa.eu/en/documents/product-information/mylotarg-epar-product-information_en.pdf (accessed on 1 Sep 2024).

121. Norsworthy, K. J. et al. FDA approval summary: mylotarg for treatment of patients with relapsed or refractory CD33-positive acute myeloid leukemia. Oncologist 23, 1103–1108 (2018).

     Article CAS PubMed PubMed Central Google Scholar 

122. He, X. et al. Bispecific and split CAR T cells targeting CD13 and TIM3 eradicate acute myeloid leukemia. Blood 135, 713–723 (2020).

     Article PubMed PubMed Central Google Scholar 

123. Godwin, C. D., McDonald, G. B. & Walter, R. B. Sinusoidal obstruction syndrome following CD33-targeted therapy in acute myeloid leukemia. Blood 129, 2330–2332 (2017).

     Article CAS PubMed PubMed Central Google Scholar 

124. Rajvanshi, P., Shulman, H. M., Sievers, E. L. & McDonald, G. B. Hepatic sinusoidal obstruction after gemtuzumab ozogamicin (mylotarg) therapy. Blood 99, 2310–2314 (2002).

     Article CAS PubMed Google Scholar 

125. Schiller, G. J. et al. Early clinical evaluation of potential synergy of targeted radiotherapy with lintuzumab-Ac225 and venetoclax in relapsed/refractory AML. Blood 140, 3336–3337 (2022).

     Article Google Scholar 

126. Abedin, S. et al. Lintuzumab-Ac225 with combination with intensive chemotherapy yields high response rate and MRD negativity in R/R AML with adverse features. Blood 140, 157–158 (2022).

     Article Google Scholar 

127. Feldman, E. J. et al. Phase III randomized multicenter study of a humanized anti-CD33 monoclonal antibody, lintuzumab, in combination with chemotherapy, versus chemotherapy alone in patients with refractory or first-relapsed acute myeloid leukemia. J. Clin. Oncol. 23, 4110–4116 (2005).

     Article CAS PubMed Google Scholar 

128. Stein, E. M. et al. A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia. Blood 131, 387–396 (2018).

     Article CAS PubMed PubMed Central Google Scholar 

129. Cortes, J. E. et al. Maturing clinical profile of IMGN779, a next-generation CD33-targeting antibody-drug conjugate, in patients with relapsed or refractory acute myeloid leukemia. Blood 132, 26 (2018).

     Article Google Scholar 

130. Ravandi, F. et al. Updated results from phase I dose-escalation study of AMG 330, a bispecific T-cell engager molecule, in patients with relapsed/refractory acute myeloid leukemia (R/R AML). J. Clin. Oncol. 38, 7508–7508 (2020).

     Article Google Scholar 

131. Krupka, C. et al. CD33 target validation and sustained depletion of AML blasts in long-term cultures by the bispecific T-cell–engaging antibody AMG 330. Blood 123, 356–365 (2014).

     Article CAS PubMed Google Scholar 

132. Subklewe, M. et al. Preliminary results from a phase 1 first-in-human study of AMG 673, a novel half-life extended (HLE) anti-CD33/CD3 BiTE® (bispecific T-cell engager) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Blood 134, 833–833 (2019).

     Article Google Scholar 

133. Marshall, A. S. J. et al. Human MICL (CLEC12A) is differentially glycosylated and is down-regulated following cellular activation. Eur. J. Immunol. 36, 2159–2169 (2006).

     Article CAS PubMed Google Scholar 

134. Chen, C.-H. et al. Dendritic-cell-associated C-type lectin 2 (DCAL-2) alters dendritic-cell maturation and cytokine production. Blood 107, 1459–1467 (2006).

     Article CAS PubMed PubMed Central Google Scholar 

135. Ngai, L. L. et al. Bimodal expression of potential drug target CLL-1 (CLEC12A) on CD34+ blasts of AML patients. Eur. J. Haematol. 107, 343–353 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

136. Zhao, X. et al. Targeting C-type lectin-like molecule-1 for antibody-mediated immunotherapy in acute myeloid leukemia. Haematologica 95, 71–78 (2010).

     Article CAS PubMed Google Scholar 

137. Bakker, A. B. H. et al. C-Type lectin-like molecule-1. Cancer Res. 64, 8443–8450 (2004).

     Article CAS PubMed Google Scholar 

138. Hutten, T. J. A. et al. CLEC12A-mediated antigen uptake and cross-presentation by human dendritic cell subsets efficiently boost tumor-reactive t cell responses. J. Immunol. 197, 2715–2725 (2016).

     Article CAS PubMed Google Scholar 

139. Toft-Petersen, M. et al. The CLEC12A receptor marks human basophils: potential implications for minimal residual disease detection in acute myeloid leukemia. Cytom. B. Clin. Cytom. 94, 520–526 (2018).

     Article CAS Google Scholar 

140. Bill, M. et al. Mapping the CLEC12A expression on myeloid progenitors in normal bone marrow; implications for understanding CLEC12A-related cancer stem cell biology. J. Cell Mol. Med. 22, 2311–2318 (2018).

     Article CAS PubMed PubMed Central Google Scholar 

141. Zloza, A. et al. NKG2D signaling on CD8+ T cells represses T-bet and rescues CD4-unhelped CD8+ T cell memory recall but not effector responses. Nat. Med. 18, 422–428 (2012).

     Article CAS PubMed PubMed Central Google Scholar 

142. Sheppard, S. et al. The immunoreceptor NKG2D promotes tumour growth in a model of hepatocellular carcinoma. Nat. Commun. 8, 13930 (2017).

     Article CAS PubMed PubMed Central Google Scholar 

143. Bauer, S. et al. Activation of NK Cells and T Cells by NKG2D, a receptor for stress-inducible MICA. Science. 285, 727–729 (1999).

     Article CAS PubMed Google Scholar 

144. Mastaglio, S. et al. Natural killer receptor ligand expression on acute myeloid leukemia impacts survival and relapse after chemotherapy. Blood Adv. 2, 335–346 (2018).

     Article CAS PubMed PubMed Central Google Scholar 

145. Salih, H. R. et al. Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. Blood 102, 1389–1396 (2003).

     Article CAS PubMed Google Scholar 

146. Zhang, T., Lemoi, B. A. & Sentman, C. L. Chimeric NK-receptor–bearing T cells mediate antitumor immunotherapy. Blood 106, 1544–1551 (2005).

     Article CAS PubMed PubMed Central Google Scholar 

147. Lanier, L. L. NKG2D Receptor and its ligands in host defense. Cancer Immunol. Res. 3, 575–582 (2015).

     Article CAS PubMed PubMed Central Google Scholar 

148. Rohner, A., Langenkamp, U., Siegler, U., Kalberer, C. P. & Wodnar-Filipowicz, A. Differentiation-promoting drugs up-regulate NKG2D ligand expression and enhance the susceptibility of acute myeloid leukemia cells to natural killer cell-mediated lysis. Leuk. Res. 31, 1393–1402 (2007).

     Article CAS PubMed Google Scholar 

149. Diermayr, S. et al. NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities. Blood 111, 1428–1436 (2008).

     Article CAS PubMed Google Scholar 

150. Themeli, M. Selecting CD7− T cells for CAR T-cell therapy. Blood 140, 2652–2653 (2022).

     Article CAS PubMed Google Scholar 

151. Watanabe, N. et al. Feasibility and preclinical efficacy of CD7-unedited CD7 CAR T cells for T cell malignancies. Mol. Ther. 31, 24–34 (2023).

     Article CAS PubMed Google Scholar 

152. Tan, Y. et al. Long-term follow-up of donor-derived CD7 CAR T-cell therapy in patients with T-cell acute lymphoblastic leukemia. J. Hematol. Oncol. 16, 34 (2023).

     Article CAS PubMed PubMed Central Google Scholar 

153. Hu, Y. et al. Genetically modified CD7-targeting allogeneic CAR-T cell therapy with enhanced efficacy for relapsed/refractory CD7-positive hematological malignancies: a phase I clinical study. Cell Res. 32, 995–1007 (2022).

     Article CAS PubMed PubMed Central Google Scholar 

154. Georgiadis, C. et al. Base-edited CAR T cells for combinational therapy against T cell malignancies. Leukemia 35, 3466–3481 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

155. Png, Y. T. et al. Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies. Blood Adv. 1, 2348–2360 (2017).

     Article CAS PubMed PubMed Central Google Scholar 

156. Lu, P. et al. Naturally selected CD7 CAR-T therapy without genetic manipulations for T-ALL/LBL: first-in-human phase i clinical trial. Blood, 140, 321–334 (2022).

157. Gomes-Silva, D. et al. CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies. Blood 130, 285–296 (2017).

     Article CAS PubMed PubMed Central Google Scholar 

158. Cao, X. et al. CD7-directed CAR T-cell therapy: a potential immunotherapy strategy for relapsed/refractory acute myeloid leukemia. Exp. Hematol. Oncol. 11, 67 (2022).

     Article CAS PubMed PubMed Central Google Scholar 

159. Muñoz, P. et al. Antigen-induced clustering of surface CD38 and recruitment of intracellular CD38 to the immunologic synapse. Blood 111, 3653–3664 (2008).

     Article PubMed Google Scholar 

160. Deterre, P. et al. CD38 in T- and B-cell functions. in Human CD38 and Related Molecules 146–168 (KARGER, 2000).

161. Terhorst, C. et al. Biochemical studies of the human thymocyte cell-surface antigens T6, T9 and T10. Cell 23, 771–780 (1981).

     Article CAS PubMed Google Scholar 

162. Keyhani, A. et al. Increased CD38 expression is associated with favorable prognosis in adult acute leukemia. Leuk. Res. 24, 153–159 (2000).

     Article CAS PubMed Google Scholar 

163. Glisovic-Aplenc, T. et al. CD38 as a pan-hematologic target for chimeric antigen receptor T cells. Blood Adv. 7, 4418–4430 (2023).

     Article CAS PubMed PubMed Central Google Scholar 

164. Facon, T. et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N. Engl. J. Med. 391, 1597–1609 (2024)

165. Attal, M. et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet 394, 2096–2107 (2019).

     Article CAS PubMed Google Scholar 

166. Baruchel, A. et al. P501: Isatuximab plus chemotherapy for pediatric relapsed/refractory acute lymphoblastic leukemia or acute myeloid leukemia (isakids): interim efficacy analysis. Hemasphere 7, e121813e (2023).

     Article PubMed Central Google Scholar 

167. Naik, J. et al. CD38 as a therapeutic target for adult acute myeloid leukemia and T-cell acute lymphoblastic leukemia. Haematologica 104, e100–e103 (2019).

     Article PubMed PubMed Central Google Scholar 

168. Van Driel, M. et al. CD44 variant isoforms are involved in plasma cell adhesion to bone marrow stromal cells. Leukemia 16, 135–143 (2002).

     Article PubMed Google Scholar 

169. Heider, K.-H., Kuthan, H., Stehle, G. & Munzert, G. CD44v6: a target for antibody-based cancer therapy. Cancer Immunol. Immunother. 53, 567–579 (2004).

     Article CAS PubMed PubMed Central Google Scholar 

170. Wang, Z., Zhao, K., Hackert, T. & Zöller, M. CD44/CD44v6 a reliable companion in cancer-initiating cell maintenance and tumor progression. Front. Cell Dev. Biol. 6, (2018).

171. Casucci, M. et al. CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma. Blood 122, 3461–3472 (2013).

     Article CAS PubMed Google Scholar 

172. Tang, L. et al. CD44v6 chimeric antigen receptor T cell specificity towards AML with FLT3 or DNMT3A mutations. Clin. Transl. Med. 12, e1007 (2022).

173. Stornaiuolo, A. et al. Characterization and functional analysis of cd44v6.car t cells endowed with a new low-affinity nerve growth factor receptor-based spacer. Hum. Gene Ther. 32, 744–760 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

174. Wu, G. et al. Preclinical evaluation of CD70-specific CAR T cells targeting acute myeloid leukemia. Front. Immunol. 14, 1093750 (2023).

175. Sauer, T. et al. CD70-specific CAR T cells have potent activity against acute myeloid leukemia without HSC toxicity. Blood 138, 318–330 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

176. Riether, C. et al. Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents. Nat. Med. 26, 1459–1467 (2020).

     Article CAS PubMed Google Scholar 

177. Mirazee, J. & Shah, N. N. CD70 CAR T cells in AML: form follows function. Cell Rep. Med. 3, 100639 (2022).

     Article CAS PubMed PubMed Central Google Scholar 

178. Daver, N., Schlenk, R. F., Russell, N. H. & Levis, M. J. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia 33, 299–312 (2019).

     Article CAS PubMed PubMed Central Google Scholar 

179. Short, N. J., Kantarjian, H., Ravandi, F. & Daver, N. Emerging treatment paradigms with FLT3 inhibitors in acute myeloid leukemia. Ther. Adv. Hematol. 10, 204062071982731 (2019).

     Article Google Scholar 

180. Erba, H. P. et al. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 401, 1571–1583 (2023).

     Article CAS PubMed Google Scholar 

181. Wang, E. S. et al. Crenolanib and intensive chemotherapy in adults with newly diagnosed FLT3-mutated AML. J. Clin. Oncol. 42, 1776–1787 (2024).

     Article CAS PubMed Google Scholar 

182. Loo, S. et al. Sorafenib plus intensive chemotherapy in newly diagnosed FLT3 -ITD AML: a randomized, placebo-controlled study by the ALLG. Blood 142, 1960–1971 (2023).

     Article CAS PubMed PubMed Central Google Scholar 

183. Chien, C. D. et al. Preclinical development of FLT3-Redirected chimeric antigen receptor T cell immunotherapy for acute myeloid leukemia. Blood 128, 1072 (2016).

     Article Google Scholar 

184. Jetani, H. et al. CAR T-cells targeting FLT3 have potent activity against FLT3−ITD+ AML and act synergistically with the FLT3-inhibitor crenolanib. Leukemia 32, 1168–1179 (2018).

     Article CAS PubMed Google Scholar 

185. Sleiman, S. et al. Anti-FLT3 CAR T cells in acute myeloid leukemia. Blood 138, 1703 (2021).

     Article Google Scholar 

186. Sommer, C. et al. Allogeneic FLT3 CAR T cells with an off-switch exhibit potent activity against AML and can be depleted to expedite bone marrow recovery. Mol. Ther. 28, 2237–2251 (2020).

     Article CAS PubMed PubMed Central Google Scholar 

187. Barneh, F. et al. Repurposing CD19-directed immunotherapies for pediatric t(8;21) acute myeloid leukemia. Haematologica 109, 4131–4136 (2024)

188. Perna, F. et al. Integrating proteomics and transcriptomics for systematic combinatorial chimeric antigen receptor therapy of AML. Cancer Cell 32, 506–519.e5 (2017).

     Article CAS PubMed PubMed Central Google Scholar 

189. Dobrowolska, H. et al. Expression of immune inhibitory receptor ILT3 in acute myeloid leukemia with monocytic differentiation. Cytom. B. Clin. Cytom. 84B, 21–29 (2013).

     Article CAS Google Scholar 

190. Loff, S. et al. Rapidly switchable universal car-t cells for treatment of CD123-positive leukemia. Mol. Ther. Oncol.17, 408–420 (2020).

     Article CAS Google Scholar 

191. Cartellieri, M. et al. Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts. Blood Cancer J. 6, e458–e458 (2016).

     Article CAS PubMed PubMed Central Google Scholar 

192. Bachmann, M. The UniCAR system: a modular CAR T cell approach to improve the safety of CAR T cells. Immunol. Lett. 211, 13–22 (2019).

     Article CAS PubMed Google Scholar 

193. Wermke, M. et al. Updated results from a phase i dose escalation study of the rapidly-switchable universal CAR-T Therapy UniCAR-T-CD123 in relapsed/refractory AML. Blood 142, 3465 (2023).

     Article Google Scholar 

194. ClinicalTrials.gov. Available online: https://clinicaltrials.gov/study/NCT05949125.

195. Sugita, M. et al. Allogeneic TCRαβ deficient CAR T-cells targeting CD123 in acute myeloid leukemia. Nat. Commun. 13, 2227 (2022).

     Article CAS PubMed PubMed Central Google Scholar 

196. Cai, T. et al. Targeting CD123 in blastic plasmacytoid dendritic cell neoplasm using allogeneic anti-CD123 CAR T cells. Nat. Commun. 13, 2228 (2022).

     Article CAS PubMed PubMed Central Google Scholar 

197. Pemmaraju, N. et al. CD123-directed allogeneic chimeric-antigen receptor T-cell therapy (CAR-T) in blastic plasmacytoid dendritic cell neoplasm (BPDCN): clinicopathological insights. Leuk. Res. 121, 106928 (2022).

     Article CAS PubMed Google Scholar 

198. Sallman, D. A. et al. Ameli-01: A phase I trial of UCART123v1.2, an anti-CD123 allogeneic CAR-T cell product, in adult patients with relapsed or refractory (R/R) CD123+ acute myeloid leukemia (AML). Blood 140, 2371–2373 (2022).

     Article Google Scholar 

199. Naik, S. et al. Safety and anti-leukemic activity of CD123-CAR T cells in pediatric patients with AML: preliminary results from a phase 1 trial. Blood 140, 4584–4585 (2022).

     Article Google Scholar 

200. Edwards, J. P. et al. Abstract 587: ACLX-002, a novel CD123-targeted universal CAR-T cell therapy for relapsed or refractory acute myeloid leukemia that can be activated and silenced in vivo with soluble protein adapters in a dose dependent manner. Cancer Res. 82, 587 (2022).

     Article Google Scholar 

201. Cummins, K. D. et al. Treating relapsed / refractory (RR) AML with biodegradable anti-CD123 CAR modified T cells. Blood 130, 1359 (2017).

     Google Scholar 

202. Budde, L. E. et al. Abstract PR14: CD123CAR displays clinical activity in relapsed/refractory (R/R) acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN): Safety and efficacy results from a phase 1 study. Cancer Immunol. Res. 8, PR14–PR14 (2020).

     Article Google Scholar 

203. Budde, L. et al. Remissions of acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm following treatment with CD123-specific CAR T cells: a first-in-human clinical trial. Blood 130, 811–811 (2017).

     Article Google Scholar 

204. Qin, H. et al. Systematic preclinical evaluation of CD33-directed chimeric antigen receptor T cell immunotherapy for acute myeloid leukemia defines optimized construct design. J. Immunother. Cancer 9, e003149 (2021).

     Article PubMed PubMed Central Google Scholar 

205. Lamba, J. K. et al. CD33 splicing SNP regulates expression levels of CD33 in normal regenerating monocytes in AML patients. Leuk. Lymphoma 59, 2250–2253 (2018).

     Article CAS PubMed PubMed Central Google Scholar 

206. Mortland, L. et al. Clinical significance of CD33 nonsynonymous single-nucleotide polymorphisms in pediatric patients with acute myeloid leukemia treated with gemtuzumab-ozogamicin–containing chemotherapy. Clin. Cancer Res. 19, 1620–1627 (2013).

     Article CAS PubMed PubMed Central Google Scholar 

207. Godwin, C. D. et al. The CD33 splice isoform lacking exon 2 as therapeutic target in human acute myeloid leukemia. Leukemia 34, 2479–2483 (2020).

     Article PubMed PubMed Central Google Scholar 

208. Shah, N. N. et al. CD33 CAR T-cells (CD33CART) for children and young adults with relapsed/refractory AML: dose-escalation results from a phase I/II multicenter trial. Blood 142, 771–771 (2023).

     Article Google Scholar 

209. Bowser, B. et al. Success of centralized manufacturing of CD33 CAR T-cells (CD33CART) for children and young adults with relapsed/refractory AML. Transplant. Cell. Ther. 30, S153–S154 (2024).

     Article Google Scholar 

210. Tambaro, F. P. et al. Autologous CD33-CAR-T cells for treatment of relapsed/refractory acute myelogenous leukemia. Leukemia 35, 3282–3286 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

211. Sallman, D. A. et al. Phase 1/1b safety study of prgn-3006 ultracar-T in patients with relapsed or refractory CD33-positive acute myeloid leukemia and higher risk myelodysplastic syndromes. Blood 140, 10313–10315 (2022).

     Article Google Scholar 

212. Pan, J. et al. Phase I study of functionally enhanced CD33 CAR T cells in patients with relapsed or refractory acute myeloid leukemia. J. Clin. Oncol. 42, 6518–6518 (2024).

     Article Google Scholar 

213. Shah, N. N. et al. Phase 1/2 Study of donor-derived anti-CD33 chimeric antigen receptor expressing T cells (VCAR33) in patients with relapsed or refractory acute myeloid leukemia after allogeneic hematopoietic cell transplantation. Blood 142, 4862 (2023).

     Article Google Scholar 

214. Appelbaum, J. et al. Drug-regulated CD33-targeted CAR T cells control AML using clinically optimized rapamycin dosing. J. Clin. Investig. 134, e169155 (2024).

215. Liu, J. et al. Targeted CD7 CAR T-cells for treatment of T-lymphocyte leukemia and lymphoma and acute myeloid leukemia: recent advances. Front. Immunol. 14, 1108959 (2023).

216. O'Hear C, et al. Anti-CD33 chimeric antigen receptor targeting of acute myeloid leukemia. Haematologica 100, 336–344 (2015).

217. Ma, Y.-J. et al. CAR-T therapy in two AML patients with post-transplant relapse and failure of anti-CD38 CAR-T cell treatment. Am. J. Cancer Res. 12, 1454–1463 (2022).

218. Wainberg, Z. A. et al. AMPLIFY-7P: Phase 1 and randomized phase 2 study of amphiphile immunotherapy ELI-002 7P as adjuvant treatment for subjects with G12D, G12R, G12V, G12C, G12A, G12S and G13D Kirsten rat sarcoma (KRAS)-mutated pancreatic ductal adenocarcinoma. J. Clin. Oncol. 42, TPS720–TPS720 (2024).

     Article Google Scholar 

219. Jin, X. et al. First-in-human phase I study of CLL-1 CAR-T cells in adults with relapsed/refractory acute myeloid leukemia. J. Hematol. Oncol. 15, 88 (2022).

     Article CAS PubMed PubMed Central Google Scholar 

220. Francica, B. et al. Abstract 6323: Preclinical evaluation of CB-012, an allogeneic anti-CLL-1 CAR-T cell therapy, that exhibits specific and potent toxicity in acute myeloid leukemia (AML) xenograft models. Cancer Res. 84, 6323–6323 (2024).

     Article Google Scholar 

221. Cui, Q. et al. CD38-directed CAR-T cell therapy: a novel immunotherapy strategy for relapsed acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation. J. Hematol. Oncol. 14, 153 (2021).

222. Hu, Y. et al. Sequential CD7 CAR T-Cell therapy and allogeneic HSCT without GVHD prophylaxis. N. Engl. J. Med. 390, 1467–1480 (2024).

     Article CAS PubMed Google Scholar 

223. Zhang, M. et al. Autologous nanobody-derived fratricide-resistant CD7-CAR T-cell therapy for patients with relapsed and refractory T-cell acute lymphoblastic leukemia/lymphoma. Clin. Cancer Res. 28, 2830–2843 (2022).

     Article CAS PubMed Google Scholar 

224. Baumeister, S. H. et al. Phase I trial of autologous CAR T cells targeting NKG2D ligands in patients with AML/MDS and multiple myeloma. Cancer Immunol. Res. 7, 100–112 (2019).

     Article CAS PubMed Google Scholar 

225. Nikiforow, S. et al. A first-in-human phase I trial of NKG2D chimeric antigen receptor-T cells in AML/MDS and multiple myeloma. J. Clin. Oncol. 34, TPS3102–TPS3102 (2016).

     Article Google Scholar 

226. Liu, F. et al. First-in-human CLL1-CD33 compound CAR (cCAR) T cell therapy in relapsed and refractory acute myeloid leukemia. EHA Library Abstract S149 (2020).

227. Levine, B. L., Miskin, J., Wonnacott, K. & Keir, C. Global manufacturing of CAR T cell therapy. Mol. Ther. Methods Clin. Dev. 4, 92–101 (2017).

     Article CAS PubMed Google Scholar 

228. Stock, S. et al. Idelalisib for optimized CD19-specific chimeric antigen receptor T cells in chronic lymphocytic leukemia patients. Int. J. Cancer 145, 1312–1324 (2019).

     Article CAS PubMed Google Scholar 

229. Casati, A. et al. Clinical-scale selection and viral transduction of human naïve and central memory CD8+ T cells for adoptive cell therapy of cancer patients. Cancer Immunol. Immunother. 62, 1563–1573 (2013).

     Article CAS PubMed PubMed Central Google Scholar 

230. Wang, X. et al. Phenotypic and functional attributes of lentivirus-modified CD19-specific human CD8+ central memory t cells manufactured at clinical scale. J. Immunother. 35, 689–701 (2012).

     Article CAS PubMed PubMed Central Google Scholar 

231. Schmueck-Henneresse, M. et al. Comprehensive approach for identifying the T cell subset origin of CD3 and CD28 antibody–activated chimeric antigen receptor-modified T cells. J. Immunother. 199, 348–362 (2017).

     CAS Google Scholar 

232. Ayala Ceja, M., Khericha, M., Harris, C. M., Puig-Saus, C. & Chen, Y. Y. CAR-T cell manufacturing: major process parameters and next-generation strategies. J. Exp. Med. 221, e20230903 (2024).

233. Roth, T. L. et al. Reprogramming human T cell function and specificity with non-viral genome targeting. Nature 559, 405–409 (2018).

     Article CAS PubMed PubMed Central Google Scholar 

234. Depil, S., Duchateau, P., Grupp, S. A., Mufti, G. & Poirot, L. “Off-the-shelf”allogeneic CAR T cells: development and challenges. Nat. Rev. Drug. Discov. 19, 185–199 (2020).

     Article CAS PubMed Google Scholar 

235. Poirot, L. et al. Multiplex genome-edited T-cell manufacturing platform for “off-the-shelf” adoptive T-cell immunotherapies. Cancer Res. 75, 3853–3864 (2015).

     Article CAS PubMed Google Scholar 

236. Vishwasrao, P., Li, G., Boucher, J. C., Smith, D. L. & Hui, S. K. Emerging CAR T cell strategies for the treatment of AML. Cancers 14, 1241 (2022).

     Article CAS PubMed PubMed Central Google Scholar 

237. Ghorashian, S. et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat. Med. 25, 1408–1414 (2019).

     Article CAS PubMed Google Scholar 

238. Watanabe, K., Kuramitsu, S., Posey, A. D. & June, C. H. Expanding the therapeutic window for CAR T cell therapy in solid tumors: the knowns and unknowns of CAR T cell biology. Front. Immunol. 9 2486 (2018).

239. Mao, R., Kong, W. & He, Y. The affinity of antigen-binding domain on the antitumor efficacy of CAR T cells: moderate is better. Front. Immunol. 13, 900241 (2022).

240. Mansilla-Soto, J. et al. HLA-independent T cell receptors for targeting tumors with low antigen density. Nat. Med. 28, 345–352 (2022).

     Article CAS PubMed PubMed Central Google Scholar 

241. Zhao, Z. et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell 28, 415–428 (2015).

     Article CAS PubMed PubMed Central Google Scholar 

242. Long, A. H. et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat. Med. 21, 581–590 (2015).

     Article CAS PubMed PubMed Central Google Scholar 

243. Hwang, M. S. et al. Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens. Nat. Commun. 12, 5271 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

244. MacKay, M. et al. The therapeutic landscape for cells engineered with chimeric antigen receptors. Nat. Biotechnol. 38, 233–244 (2020).

     Article CAS PubMed Google Scholar 

245. Hamieh, M., Mansilla-Soto, J., Rivière, I. & Sadelain, M. Programming CAR T cell tumor recognition: tuned antigen sensing and logic gating. Cancer Discov. 13, 829–843 (2023).

     Article CAS PubMed PubMed Central Google Scholar 

246. Mog, B. J. et al. Preclinical studies show that Co-STARs combine the advantages of chimeric antigen and T cell receptors for the treatment of tumors with low antigen densities. Sci. Transl. Med. 16, eadh1696 (2024).

247. Liu, Y. et al. Chimeric STAR receptors using TCR machinery mediate robust responses against solid tumors. Sci. Transl. Med. 13, eabd8636 (2021).

248. Baeuerle, P. A. et al. Synthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response. Nat. Commun. 10, 2087 (2019).

     Article PubMed PubMed Central Google Scholar 

249. Yu, L. et al. Converting TCR-based chimeric antigen receptor STAR into dual-specific targeting receptor for cancer immunotherapy. Mol. Ther. https://doi.org/10.1016/j.ymthe.2025.02.001 (2025).

250. Huang, D. et al. TCR-mimicking STAR conveys superior sensitivity over CAR in targeting tumors with low-density neoantigens. Cell Rep. 43, 114949 (2024).

     Article CAS PubMed Google Scholar 

251. Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).

     Article CAS PubMed PubMed Central Google Scholar 

252. Weber, E. W., Maus, M. V. & Mackall, C. L. The emerging landscape of immune cell therapies. Cell 181, 46–62 (2020).

     Article CAS PubMed PubMed Central Google Scholar 

253. Carnevale, J. et al. RASA2 ablation in T cells boosts antigen sensitivity and long-term function. Nature 609, 174–182 (2022).

     Article CAS PubMed PubMed Central Google Scholar 

254. Borot, F. et al. Gene-edited stem cells enable CD33-directed immune therapy for myeloid malignancies. Proc. Natl. Acad. Sci. USA 116, 11978–11987 (2019).

     Article CAS PubMed PubMed Central Google Scholar 

255. Kim, M. Y. et al. Genetic inactivation of CD33 in hematopoietic stem cells to enable CAR T cell immunotherapy for acute myeloid leukemia. Cell 173, 1439–1453.e19 (2018).

     Article CAS PubMed PubMed Central Google Scholar 

256. Liu, Y. et al. CD33-directed immunotherapy with third-generation chimeric antigen receptor T cells and gemtuzumab ozogamicin in intact and CD33-edited acute myeloid leukemia and hematopoietic stem and progenitor cells. Int. J. Cancer 150, 1141–1155 (2022).

     Article CAS PubMed Google Scholar 

257. Casirati, G. et al. Epitope editing enables targeted immunotherapy of acute myeloid leukaemia. Nature 621, 404–414 (2023).

     Article CAS PubMed PubMed Central Google Scholar 

258. Ji, R.-J. et al. Epitope prime editing shields hematopoietic cells from CD123 immunotherapy for acute myeloid leukemia. Cell Stem Cell 31, 1650–1666.e8 (2024).

     Article CAS PubMed Google Scholar 

259. Wellhausen, N. et al. Epitope base editing CD45 in hematopoietic cells enables universal blood cancer immune therapy. Sci. Transl. Med. 15, eabm2443 (2023).

260. Liu, D., Zhao, J. & Song, Y. Engineering switchable and programmable universal CARs for CAR T therapy. J. Hematol. Oncol. 12, 69 (2019).

     Article PubMed PubMed Central Google Scholar 

261. Cui, Y. et al. T lymphocytes expressing the switchable chimeric Fc receptor CD64 exhibit augmented persistence and antitumor activity. Cell Rep. 42, 112797 (2023).

     Article CAS PubMed Google Scholar 

262. Zarychta, J., Kowalczyk, A., Krawczyk, M., Lejman, M. & Zawitkowska, J. CAR-T cells immunotherapies for the treatment of acute myeloid leukemia-recent advances. Cancers 15, 2944 (2023).

     Article CAS PubMed PubMed Central Google Scholar 

263. Cho, J. H. et al. Engineering advanced logic and distributed computing in human CAR immune cells. Nat. Commun. 12, 792 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

264. Kittel-Boselli, E. et al. Targeting acute myeloid leukemia using the revCAR platform: a programmable, switchable and combinatorial strategy. Cancers 13, 4785 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

265. Lajoie, M. J. et al. Designed protein logic to target cells with precise combinations of surface antigens. Science 369, 1637–1643 (2020).

     Article CAS PubMed PubMed Central Google Scholar 

266. Roybal, K. T. et al. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164, 770–779 (2016).

     Article CAS PubMed PubMed Central Google Scholar 

267. Tousley, A. M. et al. Co-opting signalling molecules enables logic-gated control of CAR T cells. Nature 615, 507–516 (2023).

     Article CAS PubMed PubMed Central Google Scholar 

268. Cho, J. H., Collins, J. J. & Wong, W. W. Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell 173, 1426–1438.e11 (2018).

     Article CAS PubMed PubMed Central Google Scholar 

269. Allen, G. M. et al. Synthetic cytokine circuits that drive T cells into immune-excluded tumors. Science 378 (2022).

270. Zhu, I. et al. Modular design of synthetic receptors for programmed gene regulation in cell therapies. Cell 185, 1431–1443.e16 (2022).

     Article CAS PubMed PubMed Central Google Scholar 

271. Roybal, K. T. et al. Engineering T cells with customized therapeutic response programs using synthetic notch receptors. Cell 167, 419–432.e16 (2016).

     Article CAS PubMed PubMed Central Google Scholar 

272. Morsut, L. et al. Engineering customized cell sensing and response behaviors using synthetic notch receptors. Cell 164, 780–791 (2016).

     Article CAS PubMed PubMed Central Google Scholar 

273. Richards, R. M. et al. NOT-gated CD93 CAR T cells effectively target AML with minimized endothelial cross-reactivity. Blood Cancer Discov. 2, 648–665 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

274. Simon, S., Bugos, G., Salter, A. I. & Riddell, S. R. Synthetic receptors for logic gated T cell recognition and function. Curr. Opin. Immunol. 74, 9–17 (2022).

     Article CAS PubMed Google Scholar 

275. Zah, E., Lin, M.-Y., Silva-Benedict, A., Jensen, M. C. & Chen, Y. Y. T cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells. Cancer Immunol. Res. 4, 498–508 (2016).

     Article CAS PubMed PubMed Central Google Scholar 

276. Grada, Z. et al. TanCAR: A novel bispecific chimeric antigen receptor for cancer immunotherapy. Mol. Ther. Nucleic Acids 2, e105 (2013).

     Article PubMed PubMed Central Google Scholar 

277. Wang, J.-Y. & Wang, L. CAR T cell therapy: where are we now, and where are we heading? Blood sci. 5, 237–248 (2023).

278. Nelde, A. et al. Immune surveillance of acute myeloid leukemia is mediated by HLA-presented antigens on leukemia progenitor cells. Blood Cancer Discov. 4, 468–489 (2023).

     Article CAS PubMed PubMed Central Google Scholar 

279. Lynn, R. C. et al. Targeting of folate receptor β on acute myeloid leukemia blasts with chimeric antigen receptor–expressing T cells. Blood 125, 3466–3476 (2015).

     Article CAS PubMed PubMed Central Google Scholar 

280. Ross, J. F., Chaudhuri, P. K. & Ratnam, M. Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Physiologic and clinical implications. Cancer 73, 2432–2443 (1994).

     Article CAS PubMed Google Scholar 

281. Wang, H., Zheng, X., Behm, F. G. & Ratnam, M. Differentiation-independent retinoid induction of folate receptor type β, a potential tumor target in myeloid leukemia. Blood 96, 3529–3536 (2000).

     Article CAS PubMed Google Scholar 

282. Rafiq, S. et al. Optimized T-cell receptor-mimic chimeric antigen receptor T cells directed toward the intracellular Wilms Tumor 1 antigen. Leukemia 31, 1788–1797 (2017).

     Article CAS PubMed Google Scholar 

283. Di Stasi, A., Jimenez, A. M., Minagawa, K., Al-Obaidi, M. & Rezvani, K. Review of the results of WT1 peptide vaccination strategies for myelodysplastic syndromes and acute myeloid leukemia from nine different studies. Front. Immunol. 6, 236 (2015).

284. Li, Z. et al. LILRB4 ITIMs mediate the T cell suppression and infiltration of acute myeloid leukemia cells. Cell Mol. Immunol. 17, 272–282 (2020).

     Article PubMed Google Scholar 

285. Deng, M. et al. LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration. Nature 562, 605–609 (2018).

     Article CAS PubMed PubMed Central Google Scholar 

286. Yang, T. et al. LILRB4, an immune checkpoint on myeloid cells. Blood Sci. 4, 49–56 (2022).

     Article PubMed PubMed Central Google Scholar 

287. John, S. et al. A novel anti-LILRB4 CAR-T Cell for the treatment of monocytic AML. Mol. Ther. 26, 2487–2495 (2018).

     Article CAS PubMed PubMed Central Google Scholar 

288. Kang, X. et al. Inhibitory leukocyte immunoglobulin-like receptors: Immune checkpoint proteins and tumor sustaining factors. Cell Cycle 15, 25–40 (2016).

     Article CAS PubMed Google Scholar 

289. Zhao, X. et al. LILRB4 synthetic T-cell receptor and antigen receptor-T (STAR-T) for refractory/relapsed acute myeloid leukemia: first-in-human phase I clinical trial. Blood 144, 4831–4831 (2024).

     Article Google Scholar 

290. Mannis, G. N. et al. IO-202, a Novel Anti-LILRB4 antibody, with azacitidine for hypomethylating agent-naive chronic myelomonocytic leukemia: phase 1b expansion cohort results. Blood 144, 1008–1008 (2024).

     Article Google Scholar 

291. Wang, Y., Quan, Y., He, J., Chen, S. & Dong, Z. SLAM-family receptors promote resolution of ILC2-mediated inflammation. Nat. Commun. 15, 5056 (2024).

     Article CAS PubMed PubMed Central Google Scholar 

292. Radomir, L. et al. The survival and function of IL-10-producing regulatory B cells are negatively controlled by SLAMF5. Nat. Commun. 12, 1893 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

293. Pérez-Amill, L. et al. CD84: a novel target for CAR T-cell therapy for acute myeloid leukemia. Blood 140, 7379–7381 (2022).

     Article Google Scholar 

294. Ghorashian, S. & Pule, M. Siglec-6 CAR T: magic bullet for a moving target. Blood 138, 1786–1787 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

295. Jetani, H. et al. Siglec-6 is a novel target for CAR T-cell therapy in acute myeloid leukemia. Blood 138, 1830–1842 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

296. Klaihmon, P., Luanpitpong, S., Kang, X. & Issaragrisil, S. Anti-TIM3 chimeric antigen receptor-natural killer cells from engineered induced pluripotent stem cells effectively target acute myeloid leukemia cells. Cancer Cell. Int. 23, 297 (2023).

     Article CAS PubMed PubMed Central Google Scholar 

297. Wolf, Y., Anderson, A. C. & Kuchroo, V. K. TIM3 comes of age as an inhibitory receptor. Nat. Rev. Immunol. 20, 173–185 (2020).

     Article CAS PubMed Google Scholar 

298. Sabatos, C. A. et al. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat. Immunol. 4, 1102–1110 (2003).

     Article CAS PubMed Google Scholar 

299. Mandal, K. et al. Structural surfaceomics reveals an AML-specific conformation of integrin β2 as a CAR T cellular therapy target. Nat. Cancer 4, 1592–1609 (2023).

     Article CAS PubMed PubMed Central Google Scholar 

300. Blanco, B., Compte, M., Lykkemark, S., Sanz, L. & Alvarez-Vallina, L. T Cell-redirecting strategies to ‘STAb’ tumors: beyond CARs and bispecific antibodies. Trends Immunol. 40, 243–257 (2019).

     Article CAS PubMed Google Scholar 

301. Huehls, A. M., Coupet, T. A. & Sentman, C. L. Bispecific T-cell engagers for cancer immunotherapy. Immunol. Cell Biol. 93, 290–296 (2015).

     Article CAS PubMed Google Scholar 

302. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).

     Article CAS PubMed Google Scholar 

303. Liu, X. et al. Improved anti-leukemia activities of adoptively transferred T cells expressing bispecific T-cell engager in mice. Blood Cancer J. 6, e430–e430 (2016).

     Article CAS PubMed PubMed Central Google Scholar 

304. Jiménez-Reinoso, A. et al. Efficient preclinical treatment of cortical T cell acute lymphoblastic leukemia with T lymphocytes secreting anti-CD1a T cell engagers. J. Immunother. Cancer 10, e004042 (2022).

305. Velasco-Sidro, M., Arroyo-Ródenas, J., Díez-Alonso, L., Ramírez-Fernández, Á & Álvarez-Vallina, L. Dual-targeted STAb-T cells secreting BCMA and CD19 T cell engagers for improved control of haematological cancers. Oncoimmunology 14, 2444701 (2025).

     Article PubMed Google Scholar 

306. Arroyo-Rodenas, J. et al. Effect of CD22-directed CAR-T cells secreting anti-CD19 T cell engagers on control of leukemia progression compared to tandem anti-CD19/CD22 CAR-T cells. J. Clin. Oncol. 42, 2550–2550 (2024).

     Article Google Scholar 

307. Silva, H. et al. CD70 CAR T cells secreting an anti-CD33/anti-CD3 dual targeting antibody overcome antigen heterogeneity in AML. Blood 720–731 (2024).

308. Yan, Z. et al. A dual-targeting approach with anti-IL10R CAR-T cells engineered to release anti-CD33 bispecific antibody in enhancing killing effect on acute myeloid leukemia cells. Cell Oncol. 47, 1879–1895 (2024).

     Article CAS Google Scholar 

309. Silva-Santos, B., Mensurado, S. & Coffelt, S. B. γδ T cells: pleiotropic immune effectors with therapeutic potential in cancer. Nat. Rev. Cancer 19, 392–404 (2019).

     Article CAS PubMed PubMed Central Google Scholar 

310. Xin, W. et al. Structures of human γδ T cell receptor–CD3 complex. Nature 630, 222–229 (2024).

     Article CAS PubMed PubMed Central Google Scholar 

311. Sun, L., Su, Y., Jiao, A., Wang, X. & Zhang, B. T cells in health and disease. Signal Transduct. Target Ther. 8, 235 (2023).

     Article CAS PubMed PubMed Central Google Scholar 

312. Ribot, J. C., Lopes, N. & Silva-Santos, B. γδ T cells in tissue physiology and surveillance. Nat. Rev. Immunol. 21, 221–232 (2021).

     Article CAS PubMed Google Scholar 

313. Mensurado, S., Blanco-Domínguez, R. & Silva-Santos, B. The emerging roles of γδ T cells in cancer immunotherapy. Nat. Rev. Clin. Oncol. 20, 178–191 (2023).

     Article CAS PubMed Google Scholar 

314. Mensurado, S. et al. CD155/PVR determines acute myeloid leukemia targeting by Delta One T cells. Blood 143, 1488–1495 (2024).

     Article CAS PubMed PubMed Central Google Scholar 

315. Di Lorenzo, B. et al. Broad cytotoxic targeting of acute myeloid leukemia by polyclonal delta one T cells. Cancer Immunol. Res. 7, 552–558 (2019).

     Article PubMed Google Scholar 

316. Veglia, F., Perego, M. & Gabrilovich, D. Myeloid-derived suppressor cells coming of age. Nat. Immunol. 19, 108–119 (2018).

     Article CAS PubMed PubMed Central Google Scholar 

317. Li, K. et al. Myeloid-derived suppressor cells as immunosuppressive regulators and therapeutic targets in cancer. Signal Transduct. Target Ther. 6, 362 (2021).

     Article PubMed PubMed Central Google Scholar 

318. Lasser, S. A., Ozbay Kurt, F. G., Arkhypov, I., Utikal, J. & Umansky, V. Myeloid-derived suppressor cells in cancer and cancer therapy. Nat. Rev. Clin. Oncol. 21, 147–164 (2024).

     Article CAS PubMed Google Scholar 

319. Bronte, V. et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 7, 12150 (2016).

     Article CAS PubMed PubMed Central Google Scholar 

320. Di, S. et al. Combined adjuvant of Poly I:C improves antitumor effects of CAR-T cells. Front. Oncol. 9, 1208 (2019).

321. Xu, Y. et al. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood 123, 3750–3759 (2014).

     Article CAS PubMed PubMed Central Google Scholar 

322. Singh, H. et al. Reprogramming CD19-specific T cells with IL-21 signaling can improve adoptive immunotherapy of B-lineage malignancies. Cancer Res. 71, 3516–3527 (2011).

     Article CAS PubMed PubMed Central Google Scholar 

323. Avanzi, M. P. et al. IL-18 secreting CAR T cells enhance cell persistence, induce prolonged B cell aplasia and eradicate CD19+ tumor cells without need for prior conditioning. Blood 128, 816 (2016).

     Article Google Scholar 

324. Sockolosky, J. T. et al. Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes. Science 359, 1037–1042 (2018).

     Article CAS PubMed PubMed Central Google Scholar 

325. Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 9, 34 (2017).

     Article PubMed PubMed Central Google Scholar 

326. Assi, R., Kantarjian, H., Ravandi, F. & Daver, N. Immune therapies in acute myeloid leukemia: a focus on monoclonal antibodies and immune checkpoint inhibitors. Curr. Opin. Hematol. 25 111–117 (2018).

327. Williams, P. et al. The distribution of T-cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acute myeloid leukemia. Cancer 125, 1470–1481 (2019).

     Article CAS PubMed Google Scholar 

328. Mardiana, S. & Gill, S. CAR T cells for acute myeloid leukemia: state of the art and future directions. Front. Oncol. 10, 577285 (2020).

329. Song, W. & Zhang, M. Use of CAR-T cell therapy, PD-1 blockade, and their combination for the treatment of hematological malignancies. Clin. Immunol. 214, 108382 (2020).

     Article CAS PubMed Google Scholar 

330. Lemoine, J., Ruella, M. & Houot, R. Overcoming intrinsic resistance of cancer cells to CAR T-cell killing. Clin. Cancer Res. 27, 6298–6306 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

331. Karlsson, H. Approaches to augment CAR T-cell therapy by targeting the apoptotic machinery. Biochem. Soc. Trans. 44, 371–376 (2016).

     Article CAS PubMed Google Scholar 

332. Mazzone, R., Zwergel, C., Mai, A. & Valente, S. Epi-drugs in combination with immunotherapy: a new avenue to improve anticancer efficacy. Clin. Epigenet.9, 59 (2017).

     Article Google Scholar 

333. Wang, Y. et al. Low-dose decitabine priming endows CAR T cells with enhanced and persistent antitumour potential via epigenetic reprogramming. Nat. Commun. 12, 409 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

334. James, S. R., Link, P. A. & Karpf, A. R. Epigenetic regulation of X-linked cancer/germline antigen genes by DNMT1 and DNMT3b. Oncogene 25, 6975–6985 (2006).

     Article CAS PubMed Google Scholar 

335. Zhou, J. et al. Demethylating agent decitabine disrupts tumor-induced immune tolerance by depleting myeloid-derived suppressor cells. J. Cancer Res. Clin. Oncol. 143, 1371–1380 (2017).

     Article CAS PubMed Google Scholar 

336. Khan, O. et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 571, 211–218 (2019).

     Article CAS PubMed PubMed Central Google Scholar 

337. Otáhal, P. et al. Lenalidomide enhances antitumor functions of chimeric antigen receptor modified T cells. Oncoimmunology 5, e1226723 (2016).

338. Works, M. et al. Anti–B-cell maturation antigen chimeric antigen receptor T cell function against multiple myeloma is enhanced in the presence of lenalidomide. Mol. Cancer Ther. 18, 2246–2257 (2019).

     Article CAS PubMed Google Scholar 

339. Ai, K. et al. Optimizing CAR-T cell therapy for solid tumors: current challenges and potential strategies. J. Hematol. Oncol. 17, 105 (2024).

     Article PubMed PubMed Central Google Scholar 

340. PRODH2-mediated proline metabolism boosts CAR T-cell effector function. Cancer Discov. 12, 1405 (2022).

341. Ye, L. et al. A genome-scale gain-of-function CRISPR screen in CD8 T cells identifies proline metabolism as a means to enhance CAR-T therapy. Cell Metab. 34, 595–614.e14 (2022).

     Article CAS PubMed PubMed Central Google Scholar 

342. Yang, Q. et al. Superior antitumor immunotherapy efficacy of kynureninase modified CAR-T cells through targeting kynurenine metabolism. Oncoimmunology 11, 2093402 (2022).

343. Heslop, H. E. Data mining for second malignancies after CAR-T. Blood 143, 2023–2024 (2024).

     Article CAS PubMed Google Scholar 

344. Hamilton, M. P. et al. Risk of second tumors and T-cell lymphoma after CAR T-cell therapy. N. Engl. J. Med. 390, 2047–2060 (2024).

     Article CAS PubMed PubMed Central Google Scholar 

345. Strati, P. et al. Hematopoietic recovery and immune reconstitution after axicabtagene ciloleucel in patients with large B-cell lymphoma. Haematologica 106, 2667–2672 (2021).

     Article CAS PubMed Google Scholar 

346. Elsallab, M. et al. Second primary malignancies after commercial CAR T-cell therapy: analysis of the FDA adverse events reporting system. Blood 143, 2099–2105 (2024).

     Article CAS PubMed Google Scholar 

347. National Library of Medicine (US). NCT04134117. Tisagenlecleucel in primary CNS lymphoma. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT04134117?cond=NCT04134117&rank=1 (2019).

348. Frigault, M. J. et al. Tisagenlecleucel demonstrates safety, efficacy and CNS trafficking in primary CNS lymphoma. Blood 138, 258–258 (2021).

     Article Google Scholar 

349. Dietrich, J. et al. CAR-T cell therapy in recurrent primary CNS lymphoma (PCNSL): a phase 2 clinical trial (S27.009). Neurology 98, S27.009 (2022).

350. National Library of Medicine (US). NCT03630159. Study of tisagenlecleucel in combination with pembrolizumab in R/R diffuse large B-cell lymphoma patients (PORTIA). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03630159?cond=tisagenlecleucel&checkSpell=&rank=9 (2018).

351. Jaeger, U. et al. Safety and efficacy of tisagenlecleucel plus pembrolizumab in patients with R/R DLBCL: phase 1b PORTIA study results. Blood Adv. 7, 2283–2286 (2023).

     Article CAS PubMed Google Scholar 

352. National Library of Medicine (US). NCT03876028. Study of tisagenlecleucel in combination with ibrutinib in R/R diffuse large B-cell lymphoma patients. ClinicalTrials.gov . https://clinicaltrials.gov/study/NCT03876028?cond=tisagenlecleucel&checkSpell=&page=2&rank=11 (2019).

353. national library of medicine (us). nct06003179. optimizing lymphodepletion to improve outcomes in patients receiving cell therapy with kymriah (LOKI). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT06003179?cond=tisagenlecleucel&checkSpell=&page=3&rank=22 (2023).

354. National Library of Medicine (US). NCT05310591. Combination of an anti-PD1 antibody with tisagenlecleucel reinfusion in children, adolescents and young adults with acute lymphoblastic leukemia after loss of persistence (CAPTiRALL). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05310591?cond=tisagenlecleucel&checkSpell=&page=2&rank=16 (2022).

355. National Library of Medicine (US). NCT03876769. Study of efficacy and safety of tisagenlecleucel in HR B-ALL EOC MRD positive patients (CASSIOPEIA). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03876769?cond=NCT03876769&rank=1 (2018).

356. Buechner, J. et al. Chimeric antigen receptor T-cell therapy in paediatric B-cell precursor acute lymphoblastic leukaemia: curative treatment option or bridge to transplant? Front. Pediatr. 9 (2022).

357. National Library of Medicine (US). NCT03568461.Efficacy and safety of tisagenlecleucel in adult patients with refractory or relapsed follicular lymphoma (ELARA). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03568461?cond=NCT03568461&rank=1&tab=results (2018).

358. National Library of Medicine (US). NCT04234061. Clinical Trial to Assess The efficacy and safety of the combination of tisagenlecleucel and ibrutinib in mantle cell lymphoma (TARMAC). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT04234061?cond=tisagenlecleucel&checkSpell=&page=2&rank=18&tab=table (2020).

359. National Library of Medicine (U.S.). NCT02445248. Study of efficacy and safety of CTL019 in adult DLBCL patients (JULIET). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT02445248?cond=NCT02445248&rank=1 (2015).

360. Schuster, S. J. et al. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 22, 1403–1415 (2021).

     Article CAS PubMed Google Scholar 

361. National Library of Medicine (US). NCT03610724. Phase II open label trial to determine safety & efficacy of tisagenlecleucel in pediatric non-Hodgkin lymphoma patients. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03610724?cond=NCT03610724&rank=1 (2018).

362. National Library of Medicine (U.S.). NCT02228096. Study of efficacy and safety of CTL019 in pediatric ALL patients (ENSIGN). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT02228096?tab=results (2014).

363. Awasthi, R. et al. Long term durable responses in relapsed/refractory (R/R) ALL, DLBCL, and FL patients treated with tisagenlecleucel and its association with persistence of CAR T-cells. Blood 142, 4872–4872 (2023).

     Article Google Scholar 

364. Laetsch, T. W. et al. Tisagenlecleucel in pediatric and young adult patients with down syndrome-associated relapsed/refractory acute lymphoblastic leukemia. Leukemia 36, 1508–1515 (2022).

     Article CAS PubMed Google Scholar 

365. Thudium Mueller, K. et al. Tisagenlecleucel immunogenicity in relapsed/refractory acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Blood Adv. 5, 4980–4991 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

366. National Library of Medicine (US). NCT05460533. A second infusion (early reinfusion) of tisagenlecleucel in children and young adults with B-cell acute lymphoblastic leukemia(B-ALL). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05460533?cond=tisagenlecleucel&checkSpell=&page=2&rank=19 (2022).

367. National Library of Medicine (US). NCT04225676. Study of efficacy and safety of reinfusion of tisagenlecleucel in pediatric and young adult patients with acute lymphoblastic leukemia (ALL). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT04225676?cond=NCT04225676&rank=1 (2020).

368. Boyer, M. W. et al. ALL-026: evaluating efficacy and safety of tisagenlecleucel reinfusion following loss of B-cell aplasia in pediatric and young adult patients with acute lymphoblastic leukemia: HESTER phase II study. Clin. Lymphoma Myeloma Leuk. 21, S262–S263 (2021).

     Article Google Scholar 

369. Boyer, M. W. et al. HESTER: A phase II study evaluating efficacy and safety of tisagenlecleucel reinfusion in pediatric and young adult patients with acute lymphoblastic leukemia experiencing loss of B-cell aplasia. Blood 136, 23–24 (2020).

     Article Google Scholar 

370. National Library of Medicine (US). NCT04161118. Tisagenlecleucel in elderly patients with first-relapsed or primary refractory aggressive B-cell non-Hodgkin lymphoma (TIGER-CTL019). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT04161118?term=tisagenlecleucel&rank=19 (2019).

371. National Library of Medicine (US). NCT04156659. Study of tisagenlecleucel in chinese pediatric and young adult subjects with relapsed or refractory B-cell ALL. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT04156659?cond=tisagenlecleucel&checkSpell=&page=2&rank=13 (2019).

372. National Library of Medicine (US). NCT04456023. Study of tisagenlecleucel in chinese adult patients with relapsed or refractory diffuse large b-cell non-Hodgkin lymphoma (DLBCL). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT04456023?cond=tisagenlecleucel&checkSpell=&page=2&rank=17 (2020).

373. National Library of Medicine (US). NCT03570892. Tisagenlecleucel in adult patients with aggressive B-cell non-Hodgkin lymphoma. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03570892?cond=NCT03570892&rank=1 (2018).

374. Bishop, M. R. et al. Second-line tisagenlecleucel or standard care in aggressive B-cell lymphoma. N. Engl. J. Med. 386, 629–639 (2022).

     Article CAS PubMed Google Scholar 

375. National Library of Medicine (US). NCT05888493. A phase III trial comparing tisagenlecleucel to standard of care (SoC) in adult participants with R/R follicular lymphoma (LEDA). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05888493?term=tisagenlecleucel&rank=21&tab=table (2023).

376. National Library of Medicine (US). NCT04094311. Study of out of specification for tisagenlecleucel. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT04094311?cond=tisagenlecleucel&checkSpell=&rank=2.(2021)

377. National Library of Medicine (US). NCT05199961. Quality of life of adults with diffuse large B-cell lymphoma treated with tisagenlecleucel. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05199961?term=tisagenlecleucel&rank=22 (2022).

378. National Library of Medicine (US). NCT05541341. Effectiveness and safety of tisagenlecleucel therapy in brazilian patients with B-lymphocyte malignancies. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05541341?cond=tisagenlecleucel&checkSpell=&rank=6 (2022).

379. National Library of Medicine (US). NCT03153462. Axicabtagene ciloleucel expanded access study (ZUMA-9). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03153462?cond=Axicabtagene%20ciloleucel&sort=StudyFirstPostDate&rank=23 (2017).

380. Jacobson, C. A. et al. Outcomes of patients (Pts) in ZUMA-9, a multicenter, open-label study of axicabtagene ciloleucel (axi-cel) in relapsed/refractory large B cell lymphoma (R/R LBCL) for expanded access and commercial out-of-specification (OOS) product. Blood 136, 2–3 (2020).

     Article Google Scholar 

381. National Library of Medicine (US). NCT04608487. Axi-cel in CNS lymphoma. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT04608487?cond=Axicabtagene%20ciloleucel&sort=StudyFirstPostDate&rank=15 (2020).

382. Nayak, L. et al. A pilot study of axicabtagene ciloleucel (axi-cel) for relapsed/refractory primary and secondary central nervous system lymphoma (PCNSL and SCNSL). J. Clin. Oncol. 42, 2006–2006 (2024).

     Article Google Scholar 

383. National Library of Medicine (US). NCT05077527. Immune cell therapy (CAR-T) for the treatment of patients with HIV and B-cell non-Hodgkin lymphoma. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05077527?cond=Axicabtagene%20ciloleucel&sort=StudyFirstPostDate&rank=13 (2021).

384. National Library of Medicine (US). NCT05794958. Evaluate safety of axicabtagene ciloleucel reinfusion (axi-cel-2) in patients with relapsed and/or refractory second line high-risk non-Hodgkin lymphoma after standard of care Axi-Cel. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05794958?cond=NCT05794958.%20&rank=1 (2023).

385. National Library of Medicine (US). NCT05950802. Optimizing lymphodepletion to improve outcomes in patients receiving cell therapy with yescarta (ODIN). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05950802?cond=yescarta&rank=1 (2023).

386. National Library of Medicine (US). NCT03704298. Safety and efficacy of axicabtagene ciloleucel in combination with utomilumab in adults with refractory large B-cell lymphoma (ZUMA-11). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03704298?cond=Axicabtagene%20ciloleucel&sort=StudyFirstPostDate&rank=21 (2018).

387. National Library of Medicine (US). NCT04314843. Study of lenzilumab and axicabtagene ciloleucel in participants with relapsed or refractory large B-cell lymphoma (ZUMA-19). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT04314843?cond=Axicabtagene%20ciloleucel&sort=StudyFirstPostDate&rank=17 (2020).

388. Kenderian, S. S. et al. ZUMA-19: A phase 1/2 multicenter study of lenzilumab use with axicabtagene ciloleucel (axi-cel) in patients (Pts) with relapsed or refractory large B cell lymphoma (R/R LBCL). Blood 136, 6–7 (2020).

     Article Google Scholar 

389. Oluwole, O. O. et al. ZUMA-19: A phase 1/2 study of axicabtagene ciloleucel plus lenzilumab in patients with relapsed or refractory large B-cell lymphoma. Blood 140, 10318–10320 (2022).

     Article Google Scholar 

390. National Library of Medicine (US). NCT03105336. A phase 2 multicenter study of axicabtagene ciloleucel in subjects with relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03105336?cond=Axicabtagene%20ciloleucel&sort=StudyFirstPostDate&rank=24 (2017).

391. Neelapu, S. S. et al. Three-year follow-up analysis of axicabtagene ciloleucel in relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5). Blood 143, 496–506 (2024).

     Article CAS PubMed Google Scholar 

392. Ghione, P. et al. Comparative effectiveness of ZUMA-5 (axi-cel) vs SCHOLAR-5 external control in relapsed/refractory follicular lymphoma. Blood 140, 851–860 (2022).

     Article CAS PubMed PubMed Central Google Scholar 

393. Leslie, L. et al. P1159 ZUMA-24 Preliminary analysis: a phase 2 study of axicabtagene ciloleucel in the outpatient setting with prophylactic corticosteroids in patients with relapsed/refractory large B-cell lymphoma. In Eha2024 2093402 (2024).

394. Leslie, L. et al. Pb2346: ZUMA-24: a phase 2, open-label, multicenter study of axicabtagene ciloleucel in patients with relapsed/refractory large B-cell lymphoma given with corticosteroids in the outpatient setting. Hemasphere 7, e50042ff (2023).

     Article PubMed Central Google Scholar 

395. National Library of Medicine (US). NCT05459571. Study of axicabtagene ciloleucel given with steroids in participants with relapsed or refractory large B-cell lymphoma (ZUMA-24). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05459571?cond=NCT05459571&rank=1.

396. Neelapu, S. S. et al. A phase 2, open-label, multicenter study evaluating the safety and efficacy of axicabtagene ciloleucel in combination with either rituximab or lenalidomide in patients with refractory large B-cell lymphoma (ZUMA-14). Blood 134, 4093–4093 (2019).

     Article Google Scholar 

397. Strati, P. et al. Axicabtagene ciloleucel (axi-cel) in combination with rituximab (Rtx) for the treatment (Tx) of refractory large B-cell lymphoma (R-LBCL): outcomes of the phase 2 ZUMA-14 study. J. Clin. Oncol. 40, 7567–7567 (2022).

     Article Google Scholar 

398. National Library of Medicine (US). NCT04002401. Safety and efficacy of axicabtagene ciloleucel in combination with rituximab in participants with refractory large B-cell lymphoma (ZUMA-14). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT04002401?cond=Axicabtagene%20ciloleucel&sort=StudyFirstPostDate&rank=18 (2019).

399. National Library of Medicine (US). NCT03761056. Study to evaluate the efficacy and safety of axicabtagene ciloleucel as first-line therapy in participants with high-risk large B-cell lymphoma. ClinicalTrials.gov  https://clinicaltrials.gov/search?cond=Axicabtagene%20ciloleucel&sort=StudyFirstPostDate (2018).

400. Neelapu, S. S. et al. Primary analysis of ZUMA-12: a phase 2 study of axicabtagene ciloleucel (axi-cel) as first-line therapy in patients with high-risk large B-cell lymphoma (LBCL). Blood 138, 739–739 (2021).

     Article Google Scholar 

401. Neelapu, S. S. et al. Interim analysis of ZUMA-12: a phase 2 study of axicabtagene ciloleucel (axi-cel) as first-line therapy in patients (pts) with high-risk large B cell lymphoma (LBCL). Blood 136, 49–49 (2020).

     Article Google Scholar 

402. Neelapu, S. S. et al. ZUMA-12: a phase 2 multicenter study of axicabtagene ciloleucel (axi-cel) as a first-line therapy in patients (pts) with high-risk large B-cell lymphoma (LBCL). J. Clin. Oncol. 37, TPS7574–TPS7574 (2019).

     Article Google Scholar 

403. Neelapu, S. S. et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nat. Med 28, 735–742 (2022).

     Article CAS PubMed PubMed Central Google Scholar 

404. Chavez, J. C. et al. 3-year analysis of ZUMA-12: a phase 2 study of axicabtagene ciloleucel (axi-cel) as first-line therapy in patients with high-risk large B-cell lymphoma (LBCL). Blood 142, 894–894 (2023).

     Article Google Scholar 

405. National Library of Medicine (US). NCT06218602. Pilot trial of fecal microbiota transplantation for lymphoma patients receiving axicabtagene ciloleucel therapy. ClinicalTrials.gov [Internet https://clinicaltrials.gov/study/NCT06218602?cond=Axicabtagene%20ciloleucel&sort=StudyFirstPostDate&rank=4 (2024).

406. National Library of Medicine (US). NCT06043323. A phase II study of axicabtagene ciloleucel, an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in combination with radiotherapy (RT) in relapsed/refractory follicular lymphoma. ClinicalTrials.gov [Internet https://clinicaltrials.gov/study/NCT06043323?cond=Axicabtagene%20ciloleucel&sort=StudyFirstPostDate&rank=6 (2023).

407. National Library of Medicine (US). NCT06213311. A study of axicabtagene ciloleucel and glofitamab as second-line therapy for relapsed or refractory patients with large B cell lymphoma. ClinicalTrials.gov [Internet https://clinicaltrials.gov/study/NCT06213311?cond=Axicabtagene%20ciloleucel&sort=StudyFirstPostDate&rank=5 (2024).

408. National Library of Medicine (US). NCT03391466. Study of effectiveness of axicabtagene ciloleucel compared to standard of care therapy in patients with relapsed/refractory diffuse large B cell lymphoma (ZUMA-7). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03391466?cond=Axicabtagene%20ciloleucel&sort=StudyFirstPostDate&rank=22 (2017).

409. Ghobadi, A. et al. Outcomes of subsequent anti-lymphoma therapies in patients (pts) with large B-cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel) or standard of care (SOC) in the second-line (2L) ZUMA-7 study. Blood 140, 1595–1597 (2022).

     Article Google Scholar 

410. Locke, F. L. et al. Association of metabolic tumor volume (MTV) and clinical outcomes in second-line (2L) relapsed/refractory (R/R) large B-cell lymphoma (LBCL) following axicabtagene ciloleucel (axi-cel) versus standard-of-care (Soc) therapy in ZUMA-7. Blood 140, 638–640 (2022).

     Article Google Scholar 

411. Westin, J. R. et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N. Engl. J. Med. 389, 148–157 (2023).

     Article CAS PubMed Google Scholar 

412. Westin, J. R. et al. Safety and efficacy of axicabtagene ciloleucel versus standard of care in patients 65 years of age or older with relapsed/refractory large B-cell lymphoma. Clin. Cancer Res. 29, 1894–1905 (2023).

     Article CAS PubMed PubMed Central Google Scholar 

413. National Library of Medicine (US). NCT05605899. Study to compare axicabtagene ciloleucel with standard of care therapy as first-line treatment in participants with high-risk large B-cell lymphoma (ZUMA-23). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05605899?cond=NCT05605899&rank=1 (2022).

414. National Library of Medicine (US). NCT05371093. Study of axicabtagene ciloleucel versus standard of care therapy in participants with relapsed/refractory follicular lymphoma (ZUMA-22). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05371093?cond=NCT05371093&rank=1 (2022).

415. Flinn, I. W. et al. P1107: ZUMA-22: a phase 3, randomized controlled study of axicabtagene ciloleucel versus standard-of-care therapy in patients with relapsed or refractory follicular lymphoma. Hemasphere 7, e6350662 (2023).

     Article PubMed Central Google Scholar 

416. National Library of Medicine (US). NCT06609304. Axicabtagene ciloleucel for consolidation after first-line treatment of high-risk large B-cell lymphoma (axi-cel). ClinicalTrials.gov [Internet https://clinicaltrials.gov/study/NCT06609304?cond=Axicabtagene%20ciloleucel&sort=StudyFirstPostDate&rank=1 (2024).

417. National Library of Medicine (US). NCT05800067. Axi-cel retreatment in relapsed/refractory LBCL. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05800067?cond=Axicabtagene%20ciloleucel&sort=StudyFirstPostDate&rank=7 (2022).

418. Goy, A. et al. Outcomes of patients with relapsed/refractory mantle cell lymphoma (R/R MCL) treated with brexucabtagene autoleucel (brexu-cel) in ZUMA-2 and ZUMA-18, an expanded access study. Blood 142, 106–106 (2023).

     Article Google Scholar 

419. National Library of Medicine (US). NCT04162756. Study of brexucabtagene autoleucel (KTE-X19) for the treatment of individuals with relapsed/refractory B-cell malignancies (ZUMA-18). ClinicalTrials.gov  (2019).

420. NCT05776134. Expanded access study for the treatment of patients with commercially out-of-specification brexucabtagene autoleucel. ClinicalTrials.gov .

421. National Library of Medicine (US). NCT05993949. Study of brexucabtagene autoleucel plus dasatinib in adults with acute lymphoblastic leukemia. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05993949?cond=brexucabtagene%20autoleucel&rank=3 (2023).

422. Davids, M. S. et al. ZUMA-8: a phase 1 study of KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory chronic lymphocytic leukemia. Blood 140, 7454–7456 (2022).

     Article Google Scholar 

423. Flinn, I. et al. ZUMA-8: a phase 1/2 multicenter study evaluating KTE-X19 in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). J. Clin. Oncol. 37, TPS7566–TPS7566 (2019).

     Article Google Scholar 

424. National Library of Medicine (US). NCT03624036. Study to evaluate the safety and tolerability of brexucabtagene autoleucel (KTE-X19) in people with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (ZUMA-8). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03624036?cond=brexucabtagene%20autoleucel&rank=9#publications (2018).

425. National Library of Medicine (U.S.). NCT02625480. Study evaluating brexucabtagene autoleucel (KTE-X19) in pediatric and adolescent participants with relapsed/refractory B-precursor acute lymphoblastic leukemia or relapsed/refractory B-cell non-Hodgkin lymphoma (ZUMA-4). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT02625480?cond=brexucabtagene%20autoleucel&rank=10 (2015).

426. Wayne, A. S. et al. Three-year results from phase I of ZUMA-4: KTE-X19 in pediatric relapsed/refractory acute lymphoblastic leukemia. Haematologica 108, 747–760 (2022).

     Article PubMed Central Google Scholar 

427. National Library of Medicine (U.S.). NCT02614066. A study evaluating the safety and efficacy of brexucabtagene autoleucel (KTE-X19) in adult subjects with relapsed/refractory B-precursor acute lymphoblastic leukemia (ZUMA-3) (ZUMA-3). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT02614066?cond=NCT02614066&rank=1 (2015).

428. Shah, B. D. et al. KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results. Blood 138, 11–22 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

429. Shah, B. D. et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet 398, 491–502 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

430. National Library of Medicine (US). NCT06287229. Phase Ib/II study assessing the clinical activity and safety of brexucabtagene autoleucel as a consolidation in patients with relapsed/refractory (R/R) and newly diagnosed b-cell acute lymphocytic leukemia (ALL) post cytoreduction with mini-HCVD-inotuzumab-blinatumomab/HCVAD-inotuzumab-blinatumomab. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT06287229?cond=brexucabtagene%20autoleucel&rank=2 (2024).

431. National Library of Medicine (US). NCT05537766. Study of brexucabtagene autoleucel in adults with rare B-cell malignancies (ZUMA-25). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05537766?cond=brexucabtagene%20autoleucel&rank=5 (2022).

432. Wayne, A. S. et al. ZUMA-4: A phase 1/2 multicenter study evaluating the safety and efficacy of KTE-C19 (anti-CD19 CAR T cells) in pediatric and adolescent subjects with relapsed/refractory B-precursor acute lymphoblastic leukemia (R/R ALL). J. Clin. Oncol. 34, TPS7075–TPS7075 (2016).

     Article Google Scholar 

433. Wang, M. et al. ZUMA-2: Phase 2 multicenter study evaluating efficacy of kte-C19 in patients with relapsed/refractory mantle cell lymphoma. J. Clin. Oncol. 36, TPS3102–TPS3102 (2018).

     Article Google Scholar 

434. National Library of Medicine (U.S.). NCT02601313. Study of brexucabtagene autoleucel (KTE-X19) in participants with relapsed/refractory mantle cell lymphoma (cohort 1 and cohort 2) (ZUMA-2). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT02601313?cond=brexucabtagene%20autoleucel&rank=12 (2015).

435. National Library of Medicine (US). NCT06553872. Phase 2 open label randomized study of pirtobrutinib and brexucabtagene autoleucel in R/R MCL. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT06553872?cond=brexucabtagene%20autoleucel&rank=1 (2024).

436. National Library of Medicine (US). NCT04880434. Study of brexucabtagene autoleucel (KTE-X19) in participants with relapsed/refractory mantle cell lymphoma (cohort 3) (ZUMA-2). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT04880434?cond=NCT04880434&rank=1 (2021).

437. van Meerten, T. et al. Primary analysis of ZUMA-2 cohort 3: brexucabtagene autoleucel (brexu-cel) in patients (pts) with relapsed/refractory mantle cell lymphoma (R/R MCL) who were naive to bruton tyrosine kinase inhibitors (BTKi). Blood 144, 748–748 (2024).

     Article Google Scholar 

438. National Library of Medicine (US). NCT03274219. Study of bb21217 in multiple myeloma. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03274219?cond=idecabtagene%20vicleucel&rank=17 (2017).

439. Alsina, M. et al. Updated results from the phase I CRB-402 study of anti-Bcma CAR-T cell therapy bb21217 in patients with relapsed and refractory multiple myeloma: correlation of expansion and duration of response with T cell phenotypes. Blood 136, 25–26 (2020).

     Article Google Scholar 

440. National Library of Medicine (US). NCT04771078. Expanded access protocol (EAP) for participants receiving idecabtagene vicleucel that is nonconforming for commercial release. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT04771078?cond=NCT04771078&rank=1.

441. Paul, B. et al. Idecabtagene vicleucel (ide-cel) in patients (pts) with newly diagnosed multiple myeloma (NDMM) with an inadequate response to front-line autologous stem cell transplantation (ASCT): karMMa-2 cohort 2c extended follow-up. Blood 144, 3388–3388 (2024).

     Article Google Scholar 

442. National Library of Medicine (US). NCT06048250. Mezigdomide (CC-92480) post idecabtagene vicleucel in treating patients with relapsed multiple myeloma. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT06048250?cond=idecabtagene%20vicleucel&rank=7 (2023).

443. Anderson, J. L. D. et al. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, in relapsed and refractory multiple myeloma: Updated KarMMa results. J. Clin. Oncol. 39, 8016–8016 (2021).

     Article Google Scholar 

444. Raje, N. S. et al. KarMMa-7, a phase 1/2, dose-finding and dose-expansion study of combination therapies with idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy for relapsed/refractory multiple myeloma (rrmm). Blood 138, 4830–4830 (2021).

     Article Google Scholar 

445. National Library of Medicine (US). NCT04855136. Safety and efficacy of bb2121 (ide-cel) combinations in multiple myeloma (KarMMa-7). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT04855136?cond=idecabtagene%20vicleucel&rank=13 (2021).

446. National Library of Medicine (US). NCT06518551. Elotuzumab + iberdomide + dexamethasone post ide-cel in rrmm. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT06518551?cond=idecabtagene%20vicleucel&rank=3 (2024).

447. National Library of Medicine (US). NCT05032820. MM CAR-T to upgrade response BMTCTN1902. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05032820?cond=idecabtagene%20vicleucel&rank=12 (2021).

448. National Library of Medicine (US). NCT06523621. Nivolumab in multiple myeloma patients after idecabtagene vicleucel. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT06523621?cond=idecabtagene%20vicleucel&rank=2 (2024).

449. National Library of Medicine (US). NCT05393804. A study of whether ide-cel (bb2121) can be made from people with multiple myeloma who have had a hematopoietic cell transplant. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05393804?cond=idecabtagene%20vicleucel&rank=10 (2022).

450. National Library of Medicine (US). NCT06179888. Iberdomide versus observation off therapy after idecabtagene vicleucel CAR-T for multiple myeloma. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT06179888?cond=idecabtagene%20vicleucel&rank=4 (2023).

451. National Library of Medicine (US). NCT06045806. A study to compare the efficacy and safety of idecabtagene vicleucel with lenalidomide maintenance therapy versus lenalidomide maintenance therapy alone in adult participants with newly diagnosed multiple myeloma who have suboptimal response after autologous stem cell transplantation (KarMMa-9). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT06045806?cond=idecabtagene%20vicleucel&rank=8 (2023).

452. Raje, N. et al. MM-493 Efficacy and safety of idecabtagene vicleucel (ide-cel) with lenalidomide (R) maintenance versus R maintenance alone in adult patients with newly diagnosed multiple myeloma (NDMM) who have suboptimal response to autologous stem cell transplantation (ASCT): phase 3 KarMMa-9 trial. Clin. Lymphoma Myeloma Leuk. 24, S562–S563 (2024).

     Article Google Scholar 

453. National Library of Medicine (US). NCT06698887. A study to evaluate the long-term safety of idecabtagene vicleucel treatment in adults with newly diagnosed multiple myeloma in korea. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT06698887?cond=idecabtagene%20vicleucel&rank=1 (2024).

454. Abramson, J. S. et al. Two-year follow-up of lisocabtagene maraleucel in relapsed or refractory large B-cell lymphoma in TRANSCEND NHL 001. Blood 143, 404–416 (2024).

     Article CAS PubMed Google Scholar 

455. Abramson, J. S. et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood 141, 1675–1684 (2023).

     Article CAS PubMed Google Scholar 

456. Abramson, J. S. et al. Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL. J. Clin. Oncol. 36, 7505–7505 (2018).

     Article Google Scholar 

457. National Library of Medicine (US). NCT02631044. Study evaluating the safety and pharmacokinetics of JCAR017 in B-cell non-Hodgkin lymphoma (TRANSCEND-NHL-001). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT02631044?intr=Lisocabtagene%20maraleucel&rank=20 (2015).

458. Ogasawara, K. et al. In vivo cellular expansion of lisocabtagene maraleucel and association with efficacy and safety in relapsed/refractory large B-cell lymphoma. Clin. Pharm. Ther. 112, 81–89 (2022).

     Article CAS Google Scholar 

459. National Library of Medicine (US). NCT05075603. Relapsed/refractory large B-cell lymphoma with NT-I7 Post-CD19 CAR T-cell therapy. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05075603?cond=NCT05075603&rank=1 (2021).

460. Siddiqi, T. et al. Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL. Blood 139, 1794–1806 (2022).

     Article CAS PubMed Google Scholar 

461. Siddiqi, T. et al. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1–2 study. Lancet 402, 641–654 (2023).

     Article CAS PubMed PubMed Central Google Scholar 

462. National Library of Medicine (US). NCT03331198. Study evaluating safety and efficacy of JCAR017 in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03331198?intr=Lisocabtagene%20maraleucel&rank=19 (2017).

463. National Library of Medicine (US). NCT03743246. A study to evaluate the safety and efficacy of JCAR017 in pediatric subjects with relapsed/refractory (R/R) B-cell Acute Lymphoblastic Leukemia (B-ALL) and B-cell non-Hodgkin lymphoma (B-NHL). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03743246?cond=jcar017&sort=StudyFirstPostDate&limit=25&rank=5 (2018).

464. National Library of Medicine (US). NCT03483103. Lisocabtagene maraleucel (JCAR017) as SECOND-LINE THERApy (TRANSCEND-PILOT-017006). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03483103?intr=Lisocabtagene%20maraleucel&rank=18 (2018).

465. Ernst, M. et al. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database of Systematic Reviews (2021).

466. Ghosh, N. et al. Comparative effectiveness of lisocabtagene maraleucel (liso-cel) in PILOT in patients (pt) with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) for whom transplant was not intended (TNI) versus conventional second-line (2L) chemotherapy regimens in the real world. Blood 140, 10430–10431 (2022).

     Article Google Scholar 

467. National Library of Medicine (US). NCT03484702. Trial to determine the efficacy and safety of JCAR017 in adult participants with aggressive B-cell non-Hodgkin lymphoma (TRANSCENDWORLD). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03484702?intr=Lisocabtagene%20maraleucel&rank=17&tab=results (2018).

468. National Library of Medicine (US). NCT03744676. A safety trial of lisocabtagene maraleucel (JCAR017) for relapsed and refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) in the outpatient setting (TRANSCEND-OUTREACH-007). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03744676?cond=Lisocabtagene%20maraleucel&sort=StudyFirstPostDate&limit=25&page=1&rank=10 (2018).

469. Godwin, J. E. et al. Outreach: preliminary safety and efficacy results from a phase 2 study of lisocabtagene maraleucel (liso-cel) in the nonuniversity setting. J. Clin. Oncol. 39, e19513–e19513 (2021).

     Article Google Scholar 

470. Linhares, Y. et al. OUTREACH: phase 2 study of lisocabtagene maraleucel as outpatient or inpatient treatment at community sites for R/R LBCL. Blood Adv. 8, 6114–6126 (2024).

     Article CAS PubMed PubMed Central Google Scholar 

471. National Library of Medicine (US). NCT05583149. Acalabrutinib + liso-cel in R/R aggressive B-cell lymphomas. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05583149?cond=Lisocabtagene%20maraleucel&sort=StudyFirstPostDate&limit=25&page=1&rank=7 (2022).

472. National Library of Medicine (US). NCT05672173. Lisocabtagene maraleucel, nivolumab and ibrutinib for the treatment of richter’s transformation. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05672173?cond=Lisocabtagene%20maraleucel&sort=StudyFirstPostDate&limit=25&page=1&rank=4 (2023).

473. National Library of Medicine (US). NCT05873712. Zanubrutinib and lisocabtagene maraleucel for the treatment of Richter’s syndrome. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05873712?cond=Lisocabtagene%20maraleucel&sort=StudyFirstPostDate&limit=25&page=1&rank=3 (2023).

474. National Library of Medicine (US). NCT04245839. A study to evaluate the efficacy and safety of JCAR017 in adult subjects with relapsed or refractory indolent B-cell non-Hodgkin lymphoma (NHL) (TRANSCEND FL). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT04245839?cond=jcar017&sort=StudyFirstPostDate&limit=25&rank=3 (2020).

475. National Library of Medicine (US). NCT03575351. A study to compare the efficacy and safety of JCAR017 to standard of care in adult subjects with high-risk, transplant-eligible relapsed or refractory aggressive B-cell non-Hodgkin lymphomas (TRANSFORM). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03575351?cond=Lisocabtagene%20maraleucel&sort=StudyFirstPostDate&limit=25&page=1&rank=11&tab=results (2018).

476. Kamdar, M. et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet 399, 2294–2308 (2022).

     Article CAS PubMed Google Scholar 

477. Kamdar, M. K. et al. Lisocabtagene maraleucel (liso-cel) vs standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (pt) with R/R large B-cell lymphoma (LBCL): 3-year follow-up (FU) from the randomized, phase 3 TRANSFORM study. J. Clin. Oncol. 42, 7013–7013 (2024).

     Article Google Scholar 

478. National Library of Medicine (US). NCT06313996. A study to evaluate the efficacy and safety of liso-cel compared to standard of care in adults with relapsed or refractory follicular lymphoma. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT06313996?cond=Lisocabtagene%20maraleucel&sort=StudyFirstPostDate&limit=25&page=1&rank=1 (2024).

479. National Library of Medicine (US). NCT06205290. A study to compare the efficacy and safety of lisocabtagene maraleucel vs investigator’s choice options in adult participants with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, whose disease has failed treatment with both BTKi and BCL2i therapies. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT06205290?cond=Lisocabtagene%20maraleucel&sort=StudyFirstPostDate&limit=25&page=1&rank=2 (2023).

480. National Library of Medicine (US). NCT06623630. Lymphodepleting total body irradiation (TBI) plus cyclophosphamide prior to ciltacabtagene autoleucel (carvykti; cilta-cel) for multiple myeloma (MM) patients with impaired renal function. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT06623630?cond=ciltacabtagene%20autoleucel&rank=1 (2024).

481. National Library of Medicine (U.S.). NCT03090659. LCAR-B38M Cells in treating relapsed/refractory (R/R) multiple myeloma (LEGEND-2). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03090659?cond=ciltacabtagene%20autoleucel&sort=StudyFirstPostDate&limit=25&rank=15 (2017).

482. Zhao, W.-H. et al. Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: a phase 1, single-arm, open-label, multicenter study in China (LEGEND-2). J. Hematol. Oncol. 15, 86 (2022).

     Article CAS PubMed PubMed Central Google Scholar 

483. Zhao, W.-H. et al. A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. J. Hematol. Oncol. 11, 141 (2018).

     Article CAS PubMed PubMed Central Google Scholar 

484. Xu, J. et al. Long-term remission and survival in patients with relapsed or refractory multiple myeloma after treatment with LCAR-B38M CAR T cells: 5-year follow-up of the LEGEND-2 trial. J. Hematol. Oncol. 17, 23 (2024).

     Article CAS PubMed PubMed Central Google Scholar 

485. Liu, R. et al. Outcomes in patients with multiple myeloma receiving salvage treatment after BCMA -specific CAR-T therapy: A retrospective analysis of LEGEND-2. Br. J. Haematol. 204, 1780–1789 (2024).

     Article CAS PubMed Google Scholar 

486. Berdeja, J. G. et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet 398, 314–324 (2021).

     Article CAS PubMed Google Scholar 

487. National Library of Medicine (US). NCT03548207. A study of JNJ-68284528, a chimeric antigen receptor T cell (CAR-T) therapy directed against B-cell maturation antigen (BCMA) in participants with relapsed or refractory multiple myeloma (CARTITUDE-1). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03548207?cond=ciltacabtagene%20autoleucel&sort=StudyFirstPostDate&limit=25&rank=14 (2018).

488. National Library of Medicine (US). NCT05347485. A study of JNJ-68284528 out-of-specification (OOS) for commercial release in participants with multiple myeloma. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05347485?cond=ciltacabtagene%20autoleucel&rank=6 (2022).

489. National Library of Medicine (US). NCT03758417. A study of LCAR-B38M CAR-T cells, a chimeric antigen receptor T-cell (CAR-T) therapy directed against B-cell maturation antigen (BCMA) in chinese participants with relapsed or refractory multiple myeloma (CARTIFAN-1). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT03758417?cond=ciltacabtagene%20autoleucel&sort=StudyFirstPostDate&limit=25&rank=13 (2018).

490. Mi, J.-Q. et al. Phase II, open-label study of ciltacabtagene autoleucel, an anti–B-cell maturation antigen chimeric antigen receptor–T-cell therapy, in chinese patients with relapsed/refractory multiple myeloma (CARTIFAN-1). J. Clin. Oncol. 41, 1275–1284 (2023).

     Article CAS PubMed Google Scholar 

491. National Library of Medicine (US). NCT04133636. A study of JNJ-68284528, a chimeric antigen receptor T cell (CAR-T) therapy directed against B-cell maturation antigen (BCMA) in Participants with multiple myeloma (CARTITUDE-2). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT04133636?cond=ciltacabtagene%20autoleucel&rank=12 (2019).

492. Cohen, A. D. et al. Efficacy and safety of cilta-cel in patients with progressive multiple myeloma after exposure to other BCMA-targeting agents. Blood 141, 219–230 (2023).

     Article CAS PubMed Google Scholar 

493. National Library of Medicine (US). NCT06550895. A study of ciltacabtagene autoleucel and talquetamab for the treatment of participants with high-risk multiple myeloma (MonumenTAL-8). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT06550895?cond=ciltacabtagene%20autoleucel&rank=4 (2024).

494. National Library of Medicine (US). NCT06574126. Ciltacabtagene autoleucel in high-risk smoldering multiple myeloma (CAR-HiRiSMM). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT06574126?cond=ciltacabtagene%20autoleucel&rank=3 (2024).

495. National Library of Medicine (US). NCT06577025. A study of different sequences of cilta-cel, talquetamab in combination with daratumumab and teclistamab in combination with daratumumab following induction with daratumumab, bortezomib, lenalidomide and dexamethasone in participants with standard-risk newly diagnosed multiple myeloma (aMMbition). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT06577025?cond=ciltacabtagene%20autoleucel&rank=2 (2024).

496. National Library of Medicine (US). NCT04181827. A study comparing JNJ-68284528, a CAR-T therapy directed against B-cell maturation antigen (BCMA), versus pomalidomide, bortezomib and dexamethasone (pvd) or daratumumab, pomalidomide and dexamethasone (DPd) in participants with relapsed and lenalidomide-refractory multiple myeloma (CARTITUDE-4). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT04181827?cond=ciltacabtagene%20autoleucel&rank=11 (2019).

497. National Library of Medicine (US). NCT04923893. A study of bortezomib, lenalidomide and dexamethasone (VRd) followed by cilta-cel, a CAR-T therapy directed against BCMA versus VRd followed by lenalidomide and dexamethasone (Rd) therapy in participants with newly diagnosed multiple myeloma for whom ASCT is not planned as initial therapy (CARTITUDE-5). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT04923893?cond=ciltacabtagene%20autoleucel&rank=9 (2021).

498. Dytfeld, D. et al. Bortezomib, lenalidomide and dexamethasone (VRd) followed by ciltacabtagene autoleucel versus Vrd followed by lenalidomide and dexamethasone (Rd) Maintenance in patients with newly diagnosed multiple myeloma not intended for transplant: a randomized, phase 3 study (CARTITUDE-5). Blood 138, 1835–1835 (2021).

     Article Google Scholar 

499. National Library of Medicine (US). NCT05257083. A study of daratumumab, bortezomib, lenalidomide and dexamethasone (DVRd) followed by ciltacabtagene autoleucel versus daratumumab, bortezomib, lenalidomide and dexamethasone (DVRd) followed by autologous stem cell transplant (ASCT) in participants with newly diagnosed multiple myeloma (CARTITUDE-6). ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05257083?cond=ciltacabtagene%20autoleucel&rank=7 (2022).

500. National Library of Medicine (US). NCT05201781. A long-term study for participants previously treated with ciltacabtagene autoleucel. ClinicalTrials.gov  https://clinicaltrials.gov/study/NCT05201781?cond=ciltacabtagene%20autoleucel&rank=8 (2022).

501. Ehninger, G. et al. Phase 1 dose escalation study of the rapidly switchable universal CAR-T therapy Unicar-T-CD123 in relapsed/refractory AML. Blood 140, 2367–2368 (2022).

     Article Google Scholar 

502. Wermke, M. et al. Proof of concept for a rapidly switchable universal CAR-T platform with UniCAR-T-CD123 in relapsed/refractory AML. Blood 137, 3145–3148 (2021).

     Article CAS PubMed PubMed Central Google Scholar 

503. Feldmann, A. et al. A novel revcar platform for switchable and gated tumor targeting. Blood 134, 5611–5611 (2019).

     Article Google Scholar 

504. A. Ehninger, et al. Preclinical characterization of switchable allogeneic chimeric antigen receptor T cells to support first in human clinical study in CD123-positive hematologic and lymphatic malignancies. . In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4095.

505. Sallman, D. A. et al. Phase 1/1b safety study of Prgn-3006 Ultracar-T in patients with relapsed or refractory CD33-positive acute myeloid leukemia and higher risk myelodysplastic syndromes. Blood 138, 825 (2021).

     Article Google Scholar 

506. Zuo, S. et al. C-JUN overexpressing CAR-T cells in acute myeloid leukemia: preclinical characterization and phase I trial. Nat. Commun. 15, 6155 (2024).

     Article CAS PubMed PubMed Central Google Scholar 

507. Wang, Q. et al. Treatment of CD33-directed Chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Mol. Ther. 23, 184–191 (2015).

     Article CAS PubMed Google Scholar 

508. Shah N., et al. G. Phase 1/2 study of donor-derived anti-CD33 chimeric antigen receptor expressing T cells (VCAR33 ALLO) in patients with relapsed or refractory acute myeloid leukemia after allogeneic hematopoietic cell transplantation (trial in progress). Presented at the 65 th ASH annual meeting and exposition; December 9-12, San Diego, USA. 2023. Abstract nr 4862.

509. Canesin G., et al. G-CSF/plerixafor dual-mobilized donor derived CD33CAR T-cells as potent and effective AML therapy in pre-clinical models. Presented at 63rd ASH annual meeting & exposition, December 11–14, 2021. Abstract nr 1716.

510. Moeller R, K. S. S. J. Construction and evaluation of interleukin 3 (IL3)-zetakine–redirected cytolytic T cells for treatment of CD123-expressing acute myeloid leukemia. Presented at SITC 2021, November 10–14, 2021. Abstract nr 871.

511. Cooper, T. M. et al. Pediatric and young adult leukemia adoptive therapy (PLAT)-08: A phase 1 study of SC-DARIC33 in pediatric and young adults with relapsed or refractory CD33+ AML. J. Clin. Oncol. 40, TPS7078–TPS7078 (2022).

     Article Google Scholar 

512. Petrov, J. C. et al. Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia. Leukemia 32, 1317–1326 (2018).

     Article PubMed PubMed Central Google Scholar 

513. Daver, N. G. et al. A first-in-human phase 1, multicenter, open-label study of CB-012, a next-generation CRISPR-edited allogeneic anti-CLL-1 CAR-T cell therapy for adults with relapsed/refractory acute myeloid leukemia (AMpLify). J. Clin. Oncol. 42, TPS6586–TPS6586 (2024).

     Article Google Scholar 

514. Liu, F. et al. First-in-human CLL1-CD33 compound CAR T cell therapy induces complete remission in patients with refractory acute myeloid leukemia: update on phase 1 clinical trial. Blood 132, 901–901 (2018).

     Article Google Scholar 

515. Chen, L. et al. Targeting FLT3 by chimeric antigen receptor T cells for the treatment of acute myeloid leukemia. Leukemia 31, 1830–1834 (2017).

     Article CAS PubMed PubMed Central Google Scholar 

516. Karbowski, C. M. et al. Nonclinical safety assessment of AMG 553, an investigational anti-FLT3 CAR-T therapy. J. Clin. Oncol. 37, 7032–7032 (2019).

     Article Google Scholar 

517. Karbowski, C. et al. Nonclinical safety assessment of AMG 553, an investigational chimeric antigen receptor T-cell therapy for the treatment of acute myeloid leukemia. Toxicol. Sci. 177, 94–107 (2020).

     Article CAS PubMed PubMed Central Google Scholar 

518. Cui, Q. et al. Case report: CD38-directed CAR-T cell therapy: a novel immunotherapy targeting CD38-positive blasts overcomes TKI and chemotherapy resistance of myeloid chronic myeloid leukemia in blastic phase. Front. Immunol. 13, 1012981 (2022).

519. Murad, J. M. et al. Manufacturing development and clinical production of NKG2D chimeric antigen receptor–expressing T cells for autologous adoptive cell therapy. Cytotherapy 20, 952–963 (2018).

     Article CAS PubMed PubMed Central Google Scholar 

520. Carrabba, M. G. et al. Phase I-IIa clinical trial to assess safety and efficacy of MLM-CAR44.1, a CD44v6-directed CAR-T in relapsed/refractory acute myeloid leukemia (AML) and multiple myeloma (MM). Blood 132, 5790–5790 (2018).

     Article Google Scholar 

521. Salman, H. et al. Preclinical targeting of human acute myeloid leukemia using CD4-specific chimeric antigen receptor (CAR) T Cells and NK Cells. J. Cancer 10, 4408–4419 (2019).

     Article CAS PubMed PubMed Central Google Scholar 

522. Pei, K. et al. Anti-CLL1-based CAR T-cells with 4-1-BB or CD28/CD27 stimulatory domains in treating childhood refractory/relapsed acute myeloid leukemia. Cancer Med. 12, 9655–9661 (2023).

     Article CAS PubMed PubMed Central Google Scholar 

523. Zhang, H. et al. Characteristics of anti-CLL1-based CAR-T therapy for children with relapsed or refractory acute myeloid leukemia: the multi-center efficacy and safety interim analysis. Leukemia 36, 2596–2604 (2022).

     Article CAS PubMed Google Scholar 

524. Hazelton, W., Ghorashian, S. & Pule, M. Nanobody-based tri-specific chimeric antigen receptor to treat acute myeloid leukaemia. Blood 136, 10–11 (2020).

     Article Google Scholar

CAR-T cel therapie, Overzicht en stand van zaken, Acute Myeloide Leukemie, JAMA

---

• Wat houdt CAR-T celtherapie in? Zie overzicht en stand van zaken. Met extra aandacht voor CAR-T celt therapie bij Acute Myeloide Leukemie

---

• CAR-T celtherapie gericht op de CLL1 en CD33 expressie met dubbele aanpak geeft hoopvolle resultaten bij Acute Myeloide Leukemie. Een vrouw met recidief van AML na beenmergtransplantatie komt zelfs in een duurzame complete remissie

---

• CAR-T-celtherapie geneest patienten met Lupus en leukemie maar is duur, ziekmakende afweercellen wegzuigen uit bloed van proefdieren via mRNA is even effectief en goedkoper

---

• CAR-T celtherapie maakt dat kinderen met neuroblastoma nu in 2025 al meer dan 10 jaar kankervrij zijn. Met uitgelicht een prachtig overlevingsverhaal van een kind van 4 jaar die anno 2025 al 19 jaar kankervrij is.

---

• CD19 Fast-CAR-T-cel therapie bij patienten met vergevorderde B-cel acute lymfatische leukemie (B-ALL) geven hele goede resultaten bij 15 van de 20 patienten langdurige complete remissies

---

• CAR-T celtherapie brengt binnen 1 jaar al 7 van de 44 patienten met leukemie en lymfklierkanker in totale remissie in Spanje in een open gezondheidsprogramma

---

• CAR-T celtherapie is zeer succesvol bij kankerpatienten maar loopt in Nederland vast op te strenge milieueisen, stellen Nederlandse top wetenschappers copy 1

---

• Immuuntherapie met gemanipuleerde T-cellen geeft spectaculair goede resultaten bij patienten met vergevorderde leukemie en B-cel lymfomen

---

• Immuuntherapie met gemanipuleerde T-cellen - CAR-T celtherapie ( tisagenlecleucel ) geeft spectaculair goede resultaten bij patienten met gevorderde lymfklierkanker - non-Hodgkin (B-lymfomen)

---

• Dendritische celtherapie met T-car cells wordt als proef vergoed vanuit basiszorgverzekering voor melanomen stadium IIIB en IIIC

---

• Longkanker: Dendritische celtherapie plus gemoduleerde T-cellen naast chemo geeft 25 procent betere mediane overall overleving op 5 jaar bij operabele niet-kleincellige longkanker

---

• Immuuntherapie met TIL - tumor infiltrating lymfocyten zorgt bij een kwart van de deelnemers voor jarenlange ziektevrije tijd bij patienten met uitgezaaide melanomen

---

• Immuuntherapie met CAR T-Cell Therapy (tisagenlecleucel (Kymriah) goedgekeurd door FDA voor gebruik bij kinderen en jong volwassenen met vorm van Acute Lymfatische Leukemie (ALL). copy 1 copy 1

---

• Immuuntherapie met T-car cells - Tumor Lymphocytic Infiltration is interessante ontwikkeling bij verschillende vormen van kanker. Hoe meer TLI hoe beter

---

• Immuuntherapie met gemoduleerde T-car cells geeft bij zwaar voorbehandelde lymfklierkanker non-Hodgkin alsnog uitstekende resultaten met 33 en 50 procent complete remissies

---

• Receptor-gemodificeerde T-cellen leiden tot totale remissies bij uitbehandelde agressieve acute lymfatische leukemie - ALL en geven hoop op genezende behandeling. copy 1

---

• Autologe genetisch gemodificeerde T-cellen gericht tegen het humaan papillomavirus (HPV) 16 E6 geeft bij patienten met vergevorderde zwaar voorbehandelde uitgezaaide HPV gerelateerde kanker uitstekende resultaten

---

• CAR-T cel therapie is een vorm van immuuntherapie die hele goede resultaten geeft. In Jama een overzicht van stand van zaken in de klinische praktijk