Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial
Authors
- M.L. Schubert
- A. Schmitt
- A. Hückelhoven-Krauss
- B. Neuber
- A. Kunz
- P. Waldhoff
- D. Vonficht
- S. Yousefian
- L. Jopp-Saile
- L. Wang
- F. Korell
- A. Keib
- B. Michels
- D. Haas
- T. Sauer
- P. Derigs
- A. Kulozik
- J. Kunz
- P. Pavel
- S. Laier
- P. Wuchter
- J. Schmier
- G. Bug
- F. Lang
- N. Gökbuget
- J. Casper
- M. Görner
- J. Finke
- A. Neubauer
- M. Ringhoffer
- D. Wolleschak
- M. Brüggemann
- S. Haas
- A.D. Ho
- C. Müller-Tidow
- P. Dreger
- M. Schmitt
Journal
- Journal of Hematology & Oncology
Citation
- J Hematol Oncol 16 (1): 79
Abstract
BACKGROUND: Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL). METHODS: Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 106 and 50 × 106 CARTs/m2. Leukapheresis, manufacturing and administration of CARTs were performed in-house. RESULTS: For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response. CONCLUSION: In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www.clinicaltrials.gov as NCT03676504.