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CD19 CAR T Cells Following Autologous Transplantation in Poor Risk Relapsed and Refractory B cell non-Hodgkin Lymphoma

Craig S. Sauter, Brigitte Senechal, Isabelle Rivière, Ai Ni, Yvette Bernal, Xiuyan Wang, Terence Purdon, Malloury Hall, Ashvin N. Singh, Victoria Z. Szenes, Sarah Yoo, Ahmet Dogan, Yongzeng Wang, Craig H. Moskowitz, Sergio Giralt, Matthew J. Matasar, Miguel-Angel Perales, Kevin J. Curran, Jae Park, Michel Sadelain and Renier J. Brentjens

Key Points

  • 19-28z CAR-T cells following HDT-ASCT resulted in an incidence of severe neurotoxicity of 67%.

  • 19-28z CAR-T grafts with increased effector immunophenotypes trended toward protection from progression of disease following HDT-ASCT.

Abstract

High-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) is the standard of care for relapsed or chemorefractory diffuse large B-cell lymphoma (rel/ref DLBCL). Only 50% of patients are cured with this approach. We investigated whether CD19-specific chimeric antigen receptor (CAR) T cells administered following HDT-ASCT may enhance progression-free survival (PFS). Methods: Eligibility for this study includes poor-risk rel/ref aggressive B-NHL chemosensitive to salvage therapy with: 1) FDG-PET (+) or 2) bone marrow involvement. Patients underwent BEAM conditioned HDT-ASCT and followed by 19-28z CAR-T cells on days +2 and +3. Results: Of 15 subjects treated on study, dose-limiting toxicity was observed at both dose levels (5 x106 and 1 x107 19-28z CAR-T/kg). Ten of 15 subjects experienced CAR T cell-induced neurotoxicity and/or cytokine-release syndrome (CRS), which were associated with greater CAR T cell persistence (p=0.05) but not peak CAR T cell expansion. Serum IFN-g elevation (p<0.001) and possibly IL-10 (p=0.07) were associated with toxicity. The 2-year PFS is 30% (95% CI: 20-70%). Two subjects with progression of disease (POD) were CD19 (-) on re-biopsy. Subjects given decreased naïve-like (CD45RA+CCR7+) CD4+ and CD8+ CAR T cells experienced superior PFS (p=0.02 and 0.04, respectively). There was no association between CAR T cell peak expansion, persistence or cytokine changes and PFS. Conclusions: 19-28z CAR T cells following HDT-ASCT was associated with a high-incidence of reversible neurotoxicity and CRS. Following HDT-ASCT, effector CD4+ and CD8+ immunophenotypes may improve disease control. Phenotype selection and/or multiple infusions may be the focus of the next clinical trial. This study is registered at www.clinicaltrials.gov as #NCT01840566.

  • Submitted November 29, 2018.
  • Revision received June 28, 2019.
  • Accepted June 12, 2019.