Phase 1 studies of central memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL

Myeloablative autologous hematopoietic stem cell transplantation (HSCT) is a mainstay of therapy for relapsed intermediate-grade B-cell non-Hodgkin lymphoma (NHL); however, relapse rates are high. In phase 1 studies designed to improve long-term remission rates, we administered adoptive T-cell immunotherapy after HSCT, using ex vivo-expanded autologous central memory-enriched T cells (T-CM) transduced with lentivirus expressing CD19-specific chimeric antigen receptors (CARs). We present results from 2 safety/feasibility studies, NHL1 and NHL2, investigating different T-cell populations and CAR constructs. Engineered T-CM-derived CD19 CAR T cells were infused 2 days after HSCT at doses of 25 to 200 x 10(6) in a single infusion. In NHL1, 8 patients safely received T-cell products engineered from enriched CD8(+) T-CM subsets, expressing a first generation CD19 CAR containing only the CD3 zeta endodomain (CD19R:zeta). Four of 8 patients (50%; 95% confidence interval [CI]: 16-84%) were progression free at both 1 and 2 years. In NHL2, 8 patients safely received T-cell products engineered from enriched CD4(+) and CD8(+) T-CM subsets and expressing a second-generation CD19 CAR containing the CD28 and CD3 zeta endodomains (CD19R:28 zeta). Six of 8 patients (75%; 95% CI: 35-97%) were progression free at 1 year. The CD4(+)/CD8(+) T-CM-derived CD19 CAR T cells (NHL2) exhibited improvement in 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 T-CM therapy after HSCT. Trials were registered at www. clinicaltrials. gov as #NCT01318317 and #NCT01815749.