Safety and Feasibility of Anti-CD19 CAR-T Expressing IL-7 and CCL19 in Patients with Relapsed or Refractory Large B-Cell Lymphoma

Chimeric antigen receptor (CAR) T cell therapy provides a potential curative option for patients with relapsed or refractory large B-cell lymphoma (R/R LBCL). However, there are major limitations of this therapy which result in treatment resistance in B-cell malignancies, including inadequate CAR-T persistence, poor trafficking and tumor infiltration, the immunosuppressive microenvironment and frequent tumor antigen escape. Recently, several armored CAR T-cells are being developed for potential improved efficacy relative to conventional CAR T cells. Here, we engineered a CD19-spectific CAR-T cell capable of constitutive secretion of interleukin (IL)-7 and chemokine (C-C motif) ligand (CCL)-19 (7 × 19 CAR-T) and performed a multicenter phase 1b clinical trial of 7 × 19 CAR-T cell therapy in patients with R/R LBCL (NCT03929107 and NCT04833504). The 7 × 19 CAR-T cells showed that a favorable safety profile, with grade 3 cytokine release syndrome occurred in 5 (12.8%) patients and grade 3 or higher neurotoxicity occurred in 4 (10.3%) patients. The overall response rate evaluated at 3 months post-single infusion was 79.5% (complete remission, 56.4%; partial response, 23.1%). With a median follow-up of 32 months, the median progression free survival was 13 months and median overall survival was not reached, with the estimated rate of 53.8% (95% CI, 40.3% to 72.0%) at two years. Together, this long-term follow-up data from a multicenter study suggests that 7 × 19 CAR-T cells can induce durable responses with a median overall survival of greater than 2 years, and has a manageable safety profile in patients with R/R LBCL.