475. Phase I Clinical Trial of Autologous CD19-Targeted 19-28z CAR T Cells in Adult Patients With Relapsed or Refractory B-ALL
Authors: Jae H. Park, Isabelle Riviere, Xiuyan Wang, Yvette Bernal, Elizabeth Halton, Hilda Quintanilla, Kevin Curran, Craig Sauter, Michel Sadelain, Renier J. Brentjens
Journal: Molecular Therapy (2015)

Adult patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) have a dismal prognosis with a median overall survival (OS) < 6 months. Salvage chemotherapy is ineffective and often induces only a transient remission. We previously reported high anti-tumor activity of autologous T cells genetically modified to express 19-28z chimeric antigen receptor (CAR) targeting CD19 antigen in adult patients with ALL (Davila M et al. Sci Transl Med 2014). Herein, we report updated results and long-term outcome from our phase I clinical trial of 19-28z CAR T cells in adult patients with R/R ALL (NCT01044069). Adult patients with R/R B-ALL were enrolled, and underwent leukapheresis. T cells were transduced with a gamma-retroviral vector encoding a CAR construct composed of anti-CD19 scFv linked to CD28 and CD3ζ signaling domains (19-28z). All patients received lymphodepleting chemotherapy followed 2 days later by 1-3 x106 CAR T cells/kg. Bone marrow (BM) biopsy was performed immediately prior to T cell infusion for disease status assessment. 28 patients (pts) have been treated to date. The median age was 55 years (range, 23-74). 9 pts (32%) had Ph+ B-ALL (T315I mutation in 3 pts), 8 pts (29%) had prior allogeneic stem cell transplant (allo-SCT), and 22 pts (78%) had either primary refractory disease or CR1 duration of <12 months. Of the 28 pts, 27 pts were evaluable for response. At the time of 19-28z CAR T cell infusion, 14 of 27 evaluable pts had morphologic disease (>5% blasts in BM) and 13 pts had minimal residual disease (MRD). 24 of 27 pts (89%) were in complete remission (CR) following the 19-28z CAR T cell infusion; 11 of these pts had morphologic disease at the time of T cell infusion, and 13 pts had MRD. 21 of 24 CR (88%) was MRD negative. A median time to CR was 22.5 days (range, 9-33). 10 pts successfully underwent allo-HSCT following the 19-28z CAR T cell therapy. The median follow-up is 6 months (range, 1-38 months) with 15 pts having at least 6 months of follow-up. Responses appear durable with 12 pts remaining disease-free, including 7 pts without subsequent allo-SCT. Median OS of all pts is 8.5 months. While none of the 13 pts with MRD at the time of T cell infusion developed significant cytokine release syndrome (CRS), 5 of 15 pts with morphologic disease developed severe CRS that required either vasopressors or mechanical ventilation for hypoxia, successfully managed with corticosteroid and/or IL-6R inhibitor. Treatment with 19-28z CAR T cells can induce a high CR rate of 89% in these heavily pretreated adult pts with R/R ALL regardless of the disease risk characteristics including Ph+ status, age, pre-T cell disease burden, prior allo-SCT, and CR1 duration. While CRS can develop following T cell infusion, the risk of CRS predictably correlates with the disease burden and can successfully be managed with corticosteroid and/or IL-6R inhibitor. These findings support the use of 19-28z CAR T cells in adult pts with R/R ALL and warrant a further investigation in a larger phase 2 trial.