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

Abstract

Abstract Chimeric antigen receptor (CAR) T cell therapy provides a potentially 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 the inadequate CAR T cell trafficking and tumor infiltration, frequent tumor antigen escape and poor CAR T cell persistence. Here we report the development of the CD19-specific CAR T cells capable of expressing interleukin (IL)-7 and chemokine (C-C motif) ligand (CCL)-19 upon CD19 engagement (referred to as 7 × 19 CAR T cells), the preclinical study and multicenter phase 1b clinical trial of 7 × 19 CAR T cell therapy in patients with R/R LBCL (NCT03258047). The clinical trial of 7 × 19 CAR T cells showed a favorable safety profile in a cohort of R/R LBCL patients (n = 39), with grade 3 cytokine release syndrome occurred in 5 (12.8%) patients and grade 3 or higher neurotoxicity in 4 (10.3%) patients. The overall response rate 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 the median overall survival was not reached, with an estimated rate of 53.8% (95% CI, 40.3–72.0%) at two years. Together, these long-term follow-up data from the multicenter clinical study suggest that 7 × 19 CAR T cells can induce durable responses with a median overall survival of greater than 2 years, and have a manageable safety profile in patients with R/R LBCL.