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, Renier J Brentjens, 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, Renier J Brentjens
Abstract
High-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) is the standard of care for relapsed or primary refractory (rel/ref) chemorefractory diffuse large B-cell lymphoma. Only 50% of patients are cured with this approach. We investigated safety and efficacy of CD19-specific chimeric antigen receptor (CAR) T cells administered following HDT-ASCT. Eligibility for this study includes poor-risk rel/ref aggressive B-cell non-Hodgkin lymphoma chemosensitive to salvage therapy with: (1) positron emission tomography-positive disease or (2) bone marrow involvement. Patients underwent standard HDT-ASCT followed by 19-28z CAR T cells on days +2 and +3. Of 15 subjects treated on study, dose-limiting toxicity was observed at both dose levels (5 × 106 and 1 × 107 19-28z CAR T per kilogram). 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 = .05) but not peak CAR T-cell expansion. Serum interferon-γ elevation (P < .001) and possibly interleukin-10 (P = .07) were associated with toxicity. The 2-year progression-free survival (PFS) is 30% (95% confidence interval, 20% to 70%). Subjects given decreased naive-like (CD45RA+CCR7+) CD4+ and CD8+ CAR T cells experienced superior PFS (P = .02 and .04, respectively). There was no association between CAR T-cell peak expansion, persistence, or cytokine changes and PFS. 19-28z CAR T cells following HDT-ASCT were associated with a high incidence of reversible neurotoxicity and CRS. Following HDT-ASCT, effector CD4+ and CD8+ immunophenotypes may improve disease control. This trial was registered at www.clinicaltrials.gov as #NCT01840566.
Conflict of interest statement
Conflict-of-interest disclosure: C.S.S., K.J.C., and J.P. have received consulting fees and funding support from Juno Therapeutics, Inc. I.R., M.S., and R.J.B. have received consulting fees and funding support from, and are inventors of patents licensed to, Juno Therapeutics, Inc, in which they have an equity interest. The remaining authors declare no competing financial interests.
© 2019 by The American Society of Hematology.
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Source: PubMed