Clinical Efficacy and Tumor Microenvironment Influence in a Dose-Escalation Study of Anti-CD19 Chimeric Antigen Receptor T Cells in Refractory B-Cell Non-Hodgkin's Lymphoma

Purpose: Anti-CD19 chimeric antigen receptor (CAR) T cells represent a novel immunotherapy and are highly effective in treating relapsed/refractory B-cell non- Hodgkin9s lymphoma (B-NHL). How tumor microenvironment influences clinical response to CAR T therapy remains great interests. Experimental Design: Aphase 1, first-in-human, dose-escalation studyof anti-CD19 JWCAR029was conductedinrefractory B-NHL (NCT03355859)and 10 patients received CAR T cells at an escalating dose of 2.5X107(n=3), 5X107(n=4), and 1X108(n=3) cells.Core needle biopsy was performed on tumor samples collected from diffuse large B-cell lymphomapatients onDay -6 (one day before lymphodepletion) and on Day 11 after CAR T cell infusion when adequate CAR T cell expansion was detected. Results: The overall response rate was 100%, with 6 of 9 (66.7%) evaluable patients achieved complete remission. The most common adverse events of grade 3 or higher were neutropenia (10/10, 100%), anemia (3/10, 30%), thrombocytopenia (3/10, 30%), and hypofibrinogenemia (2/10, 20%). Grade 1 CRS occurred in all patientsand grade 3 neurotoxicity in one patient. The average peak levels of peripheral blood CAR T cells and cytokines were similar in three different dose levels,but CART cells were significantly higher in patients achieved CR on Day 29. Meanwhile, RNA sequencing identified gene expression signatures differentially enriched in complete and partial remission patients.Increased tumor-associated macrophage infiltration was negatively associated with remission status. Conclusions: JWCAR029was effective and safe in treating refractory B-NHL. The composition of the tumor microenvironment has a potential impact inCAR T therapy response.