Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial
Maria‐Luisa Schubert, Anita Schmitt, Angela Hückelhoven‐Krauss, Brigitte Neuber, Alexander Kunz, Philip Waldhoff, Dominik Vonficht, Schayan Yousefian, Lea Jopp‐Saile, Lei Wang, Felix Korell, Anna Keib, Birgit Michels, Dominik Haas, Tim Sauer, Patrick Derigs, Andreas E. Kulozik, Joachim B. Kunz, Petra Pavel, Sascha Laier, Patrick Wuchter, Johann W. Schmier, Gesine Bug, Fabian Lang, Nicola Gökbuget, Jochen Casper, Martin Görner, Jürgen Finke, Andreas Neubauer, Mark Ringhoffer, Denise Wolleschak, Monika Brüggemann, Simon Haas, Anthony D. Ho, Carsten Müller‐Tidow, Peter Dreger, Michael Schmitt
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: . 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.