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Phase I studies of central-memory-derived CD19 CAR T cell therapy following autologous HSCT in patients with B-cell NHL

Xiuli Wang, Leslie L. Popplewell, Jamie R. Wagner, Araceli Naranjo, M. Suzette Blanchard, Michelle R. Mott, Adam P. Norris, ChingLam W. Wong, Ryan Z. Urak, Wen-Chung Chang, Samer K. Khaled, Tanya Siddiqi, Lihua E. Budde, Jingying Xu, Brenda Chang, Nikita Gidwaney, Sandra H. Thomas, Laurence J. N. Cooper, Stanley R. Riddell, Christine E. Brown, Michael C. Jensen and Stephen J. Forman

Key points

  • TCM-derived CD19CAR T cell therapy is safe for treatment of poor-risk NHL patients undergoing autologous HSCT.

  • Addition of a CD28 costimulatory domain to the CAR, plus changes to T cell product manufacturing resulted in improved T cell expansion.

Abstract

Myeloablative autologous hematopoietic stem cell transplantation (HSCT) is a mainstay of therapy for patients with relapsed intermediate-grade B-cell non-Hodgkin lymphoma (NHL); however, relapse rates are high. In two phase I studies designed to improve long-term remission rates, we administered adoptive T-cell immunotherapy post-HSCT, utilizing ex vivo-expanded autologous central-memory-enriched T cells (TCM) transduced with lentivirus expressing CD19-specific chimeric antigen receptors (CARs). We present results from two safety/feasibility studies, NHL1 and NHL2, investigating different T cell populations and CAR constructs. Engineered TCM-derived CD19-CAR T cells were infused 2 days post-HSCT at doses of 25-200 x106 in a single infusion. In the NHL1 protocol, eight patients safely received T cell products engineered from enriched CD8+ TCM subsets, expressing a first-generation CD19 CAR containing only the CD3ζ endodomain (CD19:ζ). Four of 8 patients (50% (95% CI [16%,84%]) were progression-free at 1 and 2 years. In the NHL2 protocol, eight patients safely received T cell products engineered from enriched CD4+ and CD8+ TCM subsets and expressing a second-generation CD19 CAR containing the CD28 and CD3ζ endodomains (CD19:28ζ). Six of 8 patients (75%, 95% CI [35%,97%]) were progression-free at 1 year. The CD4+/CD8+ TCM-derived CD19 CAR T cells (NHL2) exhibited improvement in CAR T cell expansion; however, persistence was ≤28 days, similar to that seen by others using CD28 CARs. Neither cytokine release syndrome nor delayed hematopoietic engraftment was observed in either trial. These data demonstrate the safety and feasibility of CD19 CAR TCM therapy post-HSCT. Trials were registered at clinicaltrials.gov as NCT01318317 and NCT01815749.

  • Submitted December 15, 2015.
  • Accepted April 12, 2016.