Brigitte Senechal

Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia

Background CD19‐specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B‐cell acute lymphoblastic leukemia (ALL) and long‐term remissions in a subgroup of patients. Methods We conducted a phase 1 trial involving adults with relapsed B‐cell ALL who received an infusion of autologous T cells expressing the 19‐28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC). Safety and long‐term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics. Results A total of 53 adults received 19‐28z CAR T cells that were manufactured at MSKCC. After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow‐up of 29 months (range, 1 to 65), the median event‐free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event‐free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long‐term survival than did patients with a low disease burden. Conclusions In the entire cohort, the median overall survival was 12.9 months. Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19‐28z CAR T‐cell infusion than was observed among patients with a higher disease burden. (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, NCT01044069.)

Clinical and Biological Correlates of Neurotoxicity Associated with CAR T-cell Therapy in Patients with B-cell Acute Lymphoblastic Leukemia

CD19-specific chimeric antigen receptor (CAR) T-cell therapy is highly effective against relapsed or refractory acute lymphoblastic leukemia (ALL), but is hindered by neurotoxicity. In 53 adult patients with ALL, we found a significant association of severe neurotoxicity with high pretreatment disease burden, higher peak CAR T-cell expansion, and early and higher elevations of proinflammatory cytokines in blood. Patients with severe neurotoxicity had evidence of blood-cerebrospinal fluid (CSF) barrier disruption correlating with neurotoxicity grade without association with CSF white blood cell count or CAR T-cell quantity in CSF. Proinflammatory cytokines were enriched in CSF during severe neurotoxicity with disproportionately high levels of IL6, IL8, MCP1, and IP10, suggesting central nervous system-specific production. Seizures, seizure-like activity, myoclonus, and neuroimaging characteristics suggested excitatory neurotoxicity, and we found elevated levels of endogenous excitatory agonists in CSF during neurotoxicity.Significance: We detail the neurologic symptoms and blood, CSF, and neuroimaging correlates of neurotoxicity associated with CD19 CAR T cells and identify neurotoxicity risk factors. Our findings implicate cellular components other than T cells and suggest novel links between systemic inflammation and characteristic neurotoxicity symptoms. Cancer Discov; 8(8); 958-71. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 899.

Concurrent therapy of chronic lymphocytic leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia utilizing CD19-targeted CAR T-cells

Mark B. Geyer , Shwetha H. Manjunath, Andrew G. Evans, Jae H. Park, Marco L. Davila, Corey S. Cutler, Xiuyan Wang, Yongzeng Wang, Brigitte Senechal, Isabelle Rivi ere, Michel Sadelain, Jane L. Liesveld and Renier J. Brentjens Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York City, NY, USA; Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Division of Hematologic Malignancies, Dana Farber Cancer Institute, Boston, MA, USA; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York City, NY, USA; Department of Medicine, Hematology Oncology Division, Wilmot Cancer Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA