Inlichtingingen over onderstaande studie kunnen worden ingewonnen bij Zwi N. Berneman, Division of Hematology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Antwerp, Belgium; e-mail: eb.azu@namenreb.iwz.

22 maart 2021: Bron:  2017 Oct 12; 130(15): 1713–1721.

Een recidief krijgen is een groot probleem bij acute myeloïde leukemie (AML) en heeft invloed op de mediane overall overleving. Als patiënten met AML in remissie komen door chemotherapie en aansluitend dendritische celtherapie krijgen versterkt met een Wilms Tumor 1 mRNA vaccin dan blijft een remissie veel langer weg of helemaal weg dan zonder deze extra dendritische celtherapie. In een fase 2 studie onderzochten onderzoekers deze aanpak bij 30 patiënten met AML, die weliswaar in een complete remissie waren van hun AML, maar waarvan zij wisten dat die een heel hoog risico op een recidief liepen. 

Er was een aantoonbare antileukemische respons bij 13 patiënten. Negen patiënten bereikten een moleculaire remissie, zoals aangetoond door normalisatie van WT1-transcriptniveaus, waarvan er 5 duurzaam bleken na een mediane follow-up van 109,4 maanden. Stabiele ziekte werd bereikt bij 4 andere patiënten. De totale mediane overall overleving (OS) na vijf jaar was hoger bij de patiënten die goed reageerden op de dendritische celtherapie dan bij de patiënten die niet of nauwelijks reageerden. Een verdubbeling van de overall overleving op 5 jaar dus. (53,8% versus 25,0%; P = 0,01).

Bij patiënten die de dendritische cellen kregen na de 1e complete remissie, werd er bij 25 procent een recidief gezien.  De recidief vrije tijd op 5-jaars meting was stukken hoger bij responders dan bij non-responders (50% versus 7,7%; P <. 0001).
Bij patiënten van ≤ 65 jaar en > 65 jaar die DC kregen na 1e remissie, was de 5-jaars overall overleving respectievelijk 69,2% en 30,8%, vergeleken met 51,7% en 18% zoals geregistreerd in de Zweedse Acute Leukemia Registry.

An external file that holds a picture, illustration, etc.
Object name is blood780155f3.jpg

Figure 3.

Kaplan-Meier curves of the OS data. The values on the curves are 5-year relative survival from the start of WT1/DC vaccination; the values underneath in gray (A-C) are 5-year relative survival data from SEER (observed survival of newly diagnosed patients with AML included in SEER*Stat database, whereby the following case selection criteria were applied: age [minimum age, 30 years; maximum age, 79 years], race , and year of diagnosis [2005-2012]; the patient with an undefinable response was not included in panel D). For median OS (mOS), values in brackets represent median follow-up. n.r., not reached.



Het volledige studieverslag met grafieken en meer details is gratis in te zien.

Hier het abstract:

 2017 Oct 12; 130(15): 1713–1721.
Prepublished online 2017 Aug 22. doi: 10.1182/blood-2017-04-780155
PMCID: PMC5649080
PMID: 28830889

Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia



Associated Data

Supplementary Materials

Key Points

  • WT1 mRNA-electroporated DCs can prevent or delay relapse in 43% of patients with AML in remission after chemotherapy.

  • OS compares favorably with the new survival data from the Swedish Acute Leukemia Registry and correlates with molecular and WT1-specific CD8+ T-cell responses.

Abstract

Relapse is a major problem in acute myeloid leukemia (AML) and adversely affects survival. In this phase 2 study, we investigated the effect of vaccination with dendritic cells (DCs) electroporated with Wilms’ tumor 1 (WT1) messenger RNA (mRNA) as postremission treatment in 30 patients with AML at very high risk of relapse. There was a demonstrable antileukemic response in 13 patients. Nine patients achieved molecular remission as demonstrated by normalization of WT1 transcript levels, 5 of which were sustained after a median follow-up of 109.4 months. Disease stabilization was achieved in 4 other patients. Five-year overall survival (OS) was higher in responders than in nonresponders (53.8% vs 25.0%; P = .01). In patients receiving DCs in first complete remission (CR1), there was a vaccine-induced relapse reduction rate of 25%, and 5-year relapse-free survival was higher in responders than in nonresponders (50% vs 7.7%; P < .0001). In patients age ≤65 and >65 years who received DCs in CR1, 5-year OS was 69.2% and 30.8% respectively, as compared with 51.7% and 18% in the Swedish Acute Leukemia Registry. Long-term clinical response was correlated with increased circulating frequencies of polyepitope WT1-specific CD8+ T cells. Long-term OS was correlated with interferon-γ+ and tumor necrosis factor-α+ WT1-specific responses in delayed-type hypersensitivity-infiltrating CD8+ T lymphocytes. In conclusion, vaccination of patients with AML with WT1 mRNA-electroporated DCs can be an effective strategy to prevent or delay relapse after standard chemotherapy, translating into improved OS rates, which are correlated with the induction of WT1-specific CD8+ T-cell response. This trial was registered at www.clinicaltrials.gov as #NCT00965224

References

1. Howlader N, Noone AM, Krapcho M, et al. . SEER Cancer Statistics Review, 1975-2012. Bethesda, MD: National Cancer Institute; http://seer.cancer.gov/csr/1975_2012/browse_csr.php?sectionSEL=13&pageSEL=sect_13_table.16.html. Accessed 31 December 2016. []
2. Dinmohamed AG, Visser O, van Norden Y, et al. . Treatment, trial participation and survival in adult acute myeloid leukemia: a population-based study in the Netherlands, 1989-2012Leukemia. 2016;30(1):24-31. [PubMed[]
3. Ravandi F. Relapsed acute myeloid leukemia: why is there no standard of care? Best Pract Res Clin Haematol. 2013;26(3):253-259. [PMC free article] [PubMed[]
4. Anguille S, Lion E, Smits E, Berneman ZN, van Tendeloo VF. Dendritic cell vaccine therapy for acute myeloid leukemia: questions and answersHum Vaccin. 2011;7(5):579-584. [PubMed[]
5. van Besien K. Allogeneic transplantation for AML and MDS: GVL versus GVHD and disease recurrenceHematology Am Soc Hematol Educ Program. 2013;2013:56-62. [PubMed[]
6. Berneman ZN. Autologous T cells on the attack against AMLBlood. 2012;120(6):1151-1152. [PubMed[]
7. Oka Y, Tsuboi A, Taguchi T, et al. . Induction of WT1 (Wilms’ tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regressionProc Natl Acad Sci USA. 2004;101(38):13885-13890. [PMC free article] [PubMed[]
8. Rezvani K, Yong AS, Mielke S, et al. . Leukemia-associated antigen-specific T-cell responses following combined PR1 and WT1 peptide vaccination in patients with myeloid malignanciesBlood. 2008;111(1):236-242. [PMC free article] [PubMed[]
9. Maslak PG, Dao T, Krug LM, et al. . Vaccination with synthetic analog peptides derived from WT1 oncoprotein induces T-cell responses in patients with complete remission from acute myeloid leukemiaBlood. 2010;116(2):171-179. [PMC free article] [PubMed[]
10. Qazilbash MH, Wieder E, Thall PF, et al. . PR1 peptide vaccine induces specific immunity with clinical responses in myeloid malignanciesLeukemia. 2017;31(3):697-704. [PMC free article] [PubMed[]
11. Rosenblatt J, Stone RM, Uhl L, et al. . Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissionsSci Transl Med. 2016;8(368):368ra171. [PMC free article] [PubMed[]
12. Anguille S, Van Tendeloo VF, Berneman ZN. Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemiaLeukemia. 2012;26(10):2186-2196. [PubMed[]
13. Anguille S, Smits EL, Bryant C, et al. . Dendritic cells as pharmacological tools for cancer immunotherapyPharmacol Rev. 2015;67(4):731-753. [PubMed[]
14. Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN. Clinical use of dendritic cells for cancer therapyLancet Oncol. 2014;15(7):e257-e267. [PubMed[]
15. Van Tendeloo VF, Ponsaerts P, Lardon F, et al. . Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cellsBlood. 2001;98(1):49-56. [PubMed[]
16. Van Driessche A, Van de Velde AL, Nijs G, et al. . Clinical-grade manufacturing of autologous mature mRNA-electroporated dendritic cells and safety testing in acute myeloid leukemia patients in a phase I dose-escalation clinical trialCytotherapy. 2009;11(5):653-668. [PubMed[]
17. Van Tendeloo VF, Van de Velde A, Van Driessche A, et al. . Induction of complete and molecular remissions in acute myeloid leukemia by Wilms’ tumor 1 antigen-targeted dendritic cell vaccinationProc Natl Acad Sci USA. 2010;107(31):13824-13829. [PMC free article] [PubMed[]
18. Benteyn D, Anguille S, Van Lint S, et al. . Design of an optimized Wilms’ tumor 1 (WT1) mRNA construct for enhanced WT1 expression and improved immunogenicity in vitro and in vivoMol Ther Nucleic Acids. 2013;2:e134. [PMC free article] [PubMed[]
19. Ogawa H, Tamaki H, Ikegame K, et al. . The usefulness of monitoring WT1 gene transcripts for the prediction and management of relapse following allogeneic stem cell transplantation in acute type leukemiaBlood. 2003;101(5):1698-1704. [PubMed[]
20. Cilloni D, Renneville A, Hermitte F, et al. . Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: a European LeukemiaNet studyJ Clin Oncol. 2009;27(31):5195-5201. [PubMed[]
21. Inoue K, Sugiyama H, Ogawa H, et al. . WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemiaBlood. 1994;84(9):3071-3079. [PubMed[]
22. Inoue K, Ogawa H, Yamagami T, et al. . Long-term follow-up of minimal residual disease in leukemia patients by monitoring WT1 (Wilms tumor gene) expression levelsBlood. 1996;88(6):2267-2278. [PubMed[]
23. Cilloni D, Gottardi E, De Micheli D, et al. . Quantitative assessment of WT1 expression by real time quantitative PCR may be a useful tool for monitoring minimal residual disease in acute leukemia patientsLeukemia. 2002;16(10):2115-2121. [PubMed[]
24. Trka J, Kalinová M, Hrusák O, et al. ; For Czech Paediatric Haematology Working Group. Real-time quantitative PCR detection of WT1 gene expression in children with AML: prognostic significance, correlation with disease status and residual disease detection by flow cytometryLeukemia. 2002;16(7):1381-1389. [PubMed[]
25. Cilloni D, Messa F, Arruga F, et al. . Early prediction of treatment outcome in acute myeloid leukemia by measurement of WT1 transcript levels in peripheral blood samples collected after chemotherapyHaematologica. 2008;93(6):921-924. [PubMed[]
26. Cheson BD, Bennett JM, Kopecky KJ, et al. ; International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia [published correction appears in J Clin Oncol. 2004;22(3):576]J Clin Oncol. 2003;21(24):4642-4649. [PubMed[]
27. de Lima M, Strom SS, Keating M, et al. . Implications of potential cure in acute myelogenous leukemia: development of subsequent cancer and return to workBlood. 1997;90(12):4719-4724. [PubMed[]
28. Oji Y, Hashimoto N, Tsuboi A, et al. . Association of WT1 IgG antibody against WT1 peptide with prolonged survival in glioblastoma multiforme patients vaccinated with WT1 peptideInt J Cancer. 2016;139(6):1391-1401. [PMC free article] [PubMed[]
29. Rezvani K, Brenchley JM, Price DA, et al. . T-cell responses directed against multiple HLA-A*0201-restricted epitopes derived from Wilms’ tumor 1 protein in patients with leukemia and healthy donors: identification, quantification, and characterizationClin Cancer Res. 2005;11(24 Pt 1):8799-8807. [PubMed[]
30. Grimwade D, Walker H, Harrison G, et al. ; Medical Research Council Adult Leukemia Working Party. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trialBlood. 2001;98(5):1312-1320. [PubMed[]
31. Juliusson G, Lazarevic V, Hörstedt AS, Hagberg O, Höglund M; Swedish Acute Leukemia Registry Group. Acute myeloid leukemia in the real world: why population-based registries are neededBlood. 2012;119(17):3890-3899. [PMC free article] [PubMed[]
32. Keilholz U, Letsch A, Busse A, et al. . A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and MDSBlood. 2009;113(26):6541-6548. [PubMed[]
33. Wolchok JD, Hoos A, O’Day S, et al. . Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteriaClin Cancer Res. 2009;15(23):7412-7420. [PubMed[]
34. Casalegno-Garduño R, Schmitt A, Spitschak A, et al. . Immune responses to WT1 in patients with AML or MDS after chemotherapy and allogeneic stem cell transplantationInt J Cancer. 2016;138(7):1792-1801. [PubMed[]
35. Breems DA, Van Putten WL, Huijgens PC, et al. . Prognostic index for adult patients with acute myeloid leukemia in first relapseJ Clin Oncol. 2005;23(9):1969-1978. [PubMed[]
36. Wheeler CJ, Das A, Liu G, Yu JS, Black KL. Clinical responsiveness of glioblastoma multiforme to chemotherapy after vaccinationClin Cancer Res. 2004;10(16):5316-5326. [PubMed[]
37. Gribben JG, Ryan DP, Boyajian R, et al. . Unexpected association between induction of immunity to the universal tumor antigen CYP1B1 and response to next therapyClin Cancer Res. 2005;11(12):4430-4436. [PubMed[]
38. Arlen PM, Gulley JL, Parker C, et al. . A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancerClin Cancer Res. 2006;12(4):1260-1269. [PMC free article] [PubMed[]
39. Antonia SJ, Mirza N, Fricke I, et al. . Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancerClin Cancer Res. 2006;12(3 Pt 1):878-887. [PubMed[]
40. Gulley JL, Arlen PM, Tsang KY, et al. . Pilot study of vaccination with recombinant CEA-MUC-1-TRICOM poxviral-based vaccines in patients with metastatic carcinomaClin Cancer Res. 2008;14(10):3060-3069. [PMC free article] [PubMed[]
41. Chiappori AA, Soliman H, Janssen WE, Antonia SJ, Gabrilovich DI. INGN-225: a dendritic cell-based p53 vaccine (Ad.p53-DC) in small cell lung cancer: observed association between immune response and enhanced chemotherapy effectExpert Opin Biol Ther. 2010;10(6):983-991. [PMC free article] [PubMed[]
42. Schlom J, Arlen PM, Gulley JL. Cancer vaccines: moving beyond current paradigmsClin Cancer Res. 2007;13(13):3776-3782. [PMC free article] [PubMed[]
43. Madan RA, Gulley JL, Fojo T, Dahut WL. Therapeutic cancer vaccines in prostate cancer: the paradox of improved survival without changes in time to progressionOncologist. 2010;15(9):969-975. [PMC free article] [PubMed[]
44. Gulley JL, Madan RA, Schlom J. Impact of tumour volume on the potential efficacy of therapeutic vaccinesCurr Oncol. 2011;18(3):e150-e157. [PMC free article] [PubMed[]
45. van der Sluis TC, van Duikeren S, Huppelschoten S, et al. . Vaccine-induced tumor necrosis factor-producing T cells synergize with cisplatin to promote tumor cell deathClin Cancer Res. 2015;21(4):781-794. [PubMed[]
46. Brayer J, Lancet JE, Powers J, et al. . WT1 vaccination in AML and MDS: a pilot trial with synthetic analog peptidesAm J Hematol. 2015;90(7):602-607. [PMC free article] [PubMed[]
47. Wilgenhof S, Corthals J, Heirman C, et al. . Phase II study of autologous monocyte-derived mRNA electroporated dendritic cells (TriMixDC-MEL) plus ipilimumab in patients with pretreated advanced melanomaJ Clin Oncol. 2016;34(12):1330-1338. [PubMed[]
48. Fujiki F, Oka Y, Kawakatsu M, et al. . A WT1 protein-derived, naturally processed 16-mer peptide, WT1(332), is a promiscuous helper peptide for induction of WT1-specific Th1-type CD4(+) T cellsMicrobiol Immunol. 2008;52(12):591-600. [PubMed[]
49. Anguille S, Fujiki F, Smits EL, et al. . Identification of a Wilms’ tumor 1-derived immunogenic CD4(+) T-cell epitope that is recognized in the context of common Caucasian HLA-DR haplotypesLeukemia. 2013;27(3):748-750. [PubMed[]
50. National Cancer Institute: Surveillance, Epidemiology, and End Results Program: Incidence – SEER 18 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2014 Sub (1973-2012 varying)https://seer.cancer.gov/data/seerstat/nov2014/. Accessed 31 December 2016.

Articles from Blood are provided here courtesy of The American Society of Hematology

Plaats een reactie ...

Reageer op "Met WT1 mRNA versterkte dendritische cellen voorkomen recidief bij 43% van de patiënten met AML - Acute Myeloide Leukemie die in remissie kwamen na chemotherapie."


Gerelateerde artikelen
 

Gerelateerde artikelen

Met WT1 mRNA versterkte dendritische >> Anti-CD19 CAR T-celtherapie >> Nieuwe biomarkers (mutaties >> Immuuntherapie en gerichte >> Immuuntherapie met CAR T-Cell >> Twee kinderen met ongeneeslijke >> Immuuntherapie met gemanipuleerde >> Gen therapie bij leukemie >> Immuuntherapie: Vaccin geeft >> Immuuntherapie: Vaccin ontwikkelt >>