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21 oktober 2022: Bron: Blood 7 th of july 2022 en Nature

Uit een fase I studie bij oorspronkelijk 29 patiënten van 2 tot 70 jaar met vergevorderde B-cell acute lymfoblastische leukemia (B-ALL) waarvan er 20 patiënten werden geanalyseerd blijkt dat immuuntherapie met de zogeheten FasT CAR-T celtherapie (F-CAR-T) uitstekende resultaten geeft.

Van de 20 patiénten die werden geanalyseerd blijken er na 2 jaar 15 een langdurige complete remissie te hebben bereikt van mediaan 725 dagen op moment van de analyse.

1 patiënt kreeg uiteindelijk binnen de studieduur een recidief. 4 patiënten overleden als gevolg van de bijwerkingen van de allogene stamceltransplantatie die werd gedaan. CD19 F-CAR-T-cellen vertoonden uitstekende proliferatie met een jonger cellulair fenotype, minder uitputting van de T-cellen en effectievere tumoreliminatie in vergelijking met conventionele CAR-T-cellen in deze Fase I studie.

Het veiligheidsprofiel van CD19 F-CAR-T was beheersbaar met 24% graad 3 cytokine release syndrome (CRS) en 28% graad 3/4 neurotoxiciteit die voornamelijk bij pediatrische patiënten voorkwam. Op dag 14 bereikten 23/25 patiënten minimale residuele ziekte (MRD)-negatieve complete remissie (CR), en 20 ondergingen vervolgens allogene hematopoëtische stamceltransplantatie (allo-HSCT) binnen 3 maanden na F-CAR-T-therapie. Van de drie patiënten die geen allo-HSCT ondergingen, bleven er twee in CR tot 10 maanden na F-CAR-T.

FasT CAR-T celtherapie (F-CAR-T) is een vorm van CAR-T celtherapie waarbij de CAR-T cellen veel sneller aan de patiënt kan worden gegeven in vergelijking met de standaard CAR-T celtherapie. Voor gewone CAR-T cellen duurt het meestal een maand voordat deze aan de patiënt kunnen worden gegeven. Bij de FasT CAR-T celtherapie kan dat in principe direct de volgende dag. Al duurde het in deze studie nog 7 dagen voor aan alle eisen was voldaan.

De vrijgave criteria zijn samengevat in Tabel S1. Kortom, de productietijd voor F-CAR-T was de volgende dag plus nog ongeveer 7 dagen QC-tests en extra tijd voor vrijgave en transport van cellen (Fig. S1B). Maar die tijd tussen het geven van de CAR-T cellen en de stamtransplantatie is dus heel belangrijk. Hoe korter die tussentijd hoe beter. 

figure 4


Clinical outcomes and consolidative allo-HSCT for the 25 patients who were treated with F-CAR-T therapy are shown. On day 28, 23/25 patients achieved MRD-negative CR/CRi. With a median time of 54 days (range: 45–81) post F-CAR-T infusion, 20 of 23 patients with MRD-negative status received consolidative allo-HSCT. Among the 20 patients, 1 patient (F23) relapsed on day 172 and died 3 months after relapse. Four patients (F04, F09, F11, F12) died from transplant-related mortality (TRM) including infection (n = 3) and chronic GVHD (n = 1) on day 84, day 215, day 220, and day 312, respectively. The remaining 15 patients were in MRD-negative CR except for one (F18) who became MRD-positive on day 294. Among the other 3 patients (F05, F06, F16), 1 remained MRD-negative CR on day 304, 1 remained in MRD-negative CR until day 303, received allo-HSCT, and subsequently died from an infection on day 505. One patient was lost to follow-up after day 114. MRD minimal residual disease, CR complete remission, Allo-HSCT allogeneic hematopoietic stem cell transplantation.


Hier de originele Engelse tekst uit de introductie met referentieverwijzingen, daaronder het abstract:

Introduction

CD19-targeting chimeric antigen receptor-engineered T cells (CAR-T) represent a major advancement in refractory/relapsed (R/R) B-cell acute lymphocytic leukemia (B-ALL) with high initial complete remission (CR) rate of around 70–90% [1,2,3,4,5,6,7,8]. However, current CAR-T cell manufacturing requires a long waiting time for patients, typically requiring a minimum of 7–14 days of manufacturing time [9,10,11,12].
Two recent large-scale CD19-targeted CAR-T clinical trials [9, 11] reported that 20–30% of enrolled patients with B-ALL ultimately were not infused with CAR-T cells due to death from rapid disease progression or CAR-T cell manufacturing failure. Thus, shortening the duration between apheresis and CAR-T infusion is critical for patients with R/R B-ALL. Furthermore, the high cost of commercially available CAR-T cell products creates a major access barrier and limits its broad application for patients who could benefit from this novel therapeutic technology.

Notably, about 28–43% of B-ALL patients who achieve CR after CAR-T cell treatment relapse, highlighting the importance of optimizing the duration of remission after CAR-T treatment. Prolonged ex vivo culture and expansion of T- cells are associated with reduced lifespan and potency of CAR-T after adoptive transfer [13,14,15,16,17]. A recent study [18] reported that CAR-T cells manufactured within 3 days exerted enhanced proliferative capacity and increased anti-leukemia as compared to those produced within 5 or 9 days in a preclinical study. However, the feasibility of accelerated CAR-T production and its efficacy and potency in the clinic have not been widely tested [9,10,11].

To shorten the manufacturing time, minimize the cost, and optimize the function of CAR-T cell therapy, the novel anti-CD19 CAR-T therapy called FasT CAR-T (F-CAR-T) was developed with a significantly expedited CAR-T next-day manufacturing process. Here, we describe the preclinical and phase I clinical study of CD19 F-CAR-T therapy in R/R B-ALL patients.

Next-day manufacture of a novel anti-CD19 CAR-T therapy for B-cell acute lymphoblastic leukemia: first-in-human clinical study

Blood Cancer Journal volume 12, Article number: 104 (2022) Cite this article


Abstract

To improve clinical outcomes and shorten the vein-to-vein time of chimeric antigen receptor T (CAR-T) cells, we developed the FasT CAR-T (F-CAR-T) next-day manufacturing platform. We report the preclinical and first-in-human clinical studies evaluating the safety, feasibility, and preliminary efficacy of CD19 F-CAR-T in B-cell acute lymphoblastic leukemia (B-ALL). CD19 F-CAR-T cells demonstrated excellent proliferation with a younger cellular phenotype, less exhaustion, and more effective tumor elimination compared to conventional CAR-T cells in the preclinical study. In our phase I study (NCT03825718), F-CAR-T cells were successfully manufactured and infused in all of the 25 enrolled pediatric and adult patients with B-ALL. CD19 F-CAR-T safety profile was manageable with 24% grade 3 cytokine release syndrome (CRS) and 28% grade 3/4 neurotoxicity occurring predominantly in pediatric patients. On day 14, 23/25 patients achieved minimal residual disease (MRD)-negative complete remission (CR), and 20 subsequently underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) within 3 months post F-CAR-T therapy. Fifteen of 20 patients were disease-free with a median remission duration of 734 days. One patient relapsed and 4/20 died from transplant-related mortality. Of the three patients who did not undergo allo-HSCT, two remained in CR until 10 months post-F-CAR-T. Our data indicate that anti-CD19 FasT CAR-T shows promising early efficacy for B-ALL. Further evaluations in larger clinical studies are needed.

Data availability

To get a detailed protocol on the clinical trial, please find it at https://clinicaltrials.gov, NCT03825718. For any information regarding this manuscript, please contact the corresponding author at peihua_lu@126.com.

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Acknowledgements

We are indebted to the courageous patients who participated in this study and their families. We greatly appreciate the staff in the laboratory for immunotherapy from Lu Daopei Hospital and Gracell who performed the CAR-T-related tests and cytokine analyses, and the physicians in the department of HSCT for providing clinical consultation and care, and all the nurses for their devotion and patient care. We want to thank Gracell Biotechnologies Co., Ltd and their staff that provided the CAR-T products.

Author information

Author notes

  1. These authors contributed equally: Junfang Yang, Jiaping He, Xian Zhang.

Authors and Affiliations

  1. Hebei Yanda Lu Daopei Hospital, Langfang, Hebei, China

    Junfang Yang, Xian Zhang, Jingjing Li, Liyuan Qiu & Peihua Lu

  2. Beijing Lu Daopei Institute of Hematology, Beijing, China

    Junfang Yang, Xian Zhang, Jingjing Li & Peihua Lu

  3. Gracell Biotechnologies Co., Ltd, Shanghai, China

    Jiaping He, Zhenguang Wang, Yongliang Zhang, Qionglu Wu, Zhe Sun, Xun Ye, Wenjie Yin, Wei Cao, Lianjun Shen & Martina Sersch

Contributions

PL, JY, XZ and Gracell Biotechnologies Clinical science department designed the clinical study. PL, JY and XZ conducted the clinical study and provided patient care. JH is a major contributor in developing the Fast CAR-T manufacturing platform. LS, YZ and WY are the major contributors in the preclinical studies. QW recorded the case report form. ZS is a major contributor in manufacturing F-CAR-T cell product. LS, XY and LQ performed the flow cytometry, qPCR and cytokine tests. ZW and JL are major contributors in analyzing clinical data. PL, SM, LS, JY, XZ, JL, WC and ZW analyzed the data, wrote and revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Lianjun Shen or Peihua Lu.

Ethics declarations

Competing interests

JH, WC, QW, ZS, WY, LS, and MS are employees of Gracell Biotechnologies Co., Ltd. YZ, ZW, and XY were employees of Gracell Biotechnologies Co., Ltd. The other authors declare no competing interests.

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CD19 Fast-CAR-T-celtherapie, B-cel acute lymfatische leukemie (B-ALL), CAR-T cel therapie, ziektevrije tijd, complete remissie, overall overleving, stamceltransplantatie, beenmergtransplantatie


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