Determinants of response to CAR T cell therapy in a multicenter, multi-trial cohort analysis of patients with lymphoma.

In patients with non-Hodgkin lymphoma (NHL) treated with chimeric antigen receptor (CAR) T cell therapy, factors associated with efficacy overlap with prognostic biomarkers. Currently, there is no consensus on optimal product characteristics. We analyzed the phenotypic attributes of the anti-CD19 CAR T therapy axicabtagene ciloleucel (axi-cel) from 580 patients with NHL across multiple clinical trials with long-term follow-up (median, 41.9 months). A high proportion of naive-like (CCR7 + CD45RA + ) T cells was the most significant feature associated with prolonged progression-free survival (PFS; hazard ratio = 0.46, 95% confidence interval: 0.31-0.68, P = 9.8 × 10 -5 , high versus low naive-like T cell groups) without impacting safety. The relationship between naive-like T cells and efficacy was independent of tumor microenvironment characteristics (assessed in 112 patients). In multivariate models, the naive-like phenotype outperformed clinicopathologic features such as inflammatory markers and tumor burden, remaining significant after adjusting for product expansion. An inverse correlation was observed between prior lines of therapy and the proportion of naive-like T cells in both product and matched apheresis samples, suggesting a benefit of earlier intervention. The key findings were validated in an independent cohort of 203 patients treated with axi-cel-based therapy or brexucabtagene autoleucel. Mass cytometry by time-of-flight analysis of products from a subgroup of 116 patients confirmed an association between a CD8 naive-like T cell phenotype lacking expression of exhaustion markers, such as TIGIT, LAG-3 and PD-1, and PFS. The evidence generated by this study has the potential to advance the development of more effective cellular therapies.