Data from Single-cell RNA analysis reveals cell-intrinsic functions of CAR-T cells correlating with response in a phase II study of lymphoma patients

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Abstract Purpose: Although CD19 CAR-T cell therapy has shown remarkable success in B cell malignancies, a substantial fraction of patients does not obtain a long-term clinical response. This could be influenced by the quality of the individual CAR-T infusion product. To shed some light on this, clinical outcome was correlated to characteristics of CAR-T cell infusion products. Patients and Methods: In this phase II study patients with B cell lymphoma (n=23) or leukemia (n=1) received one or two infusions of third generation CD19-directed CAR-T cells (2x108/m2). The clinical trial was registered at clinicaltrials.gov: NCT03068416. We investigated the transcriptional profile of individual third generation CD19 CAR-T infusion products using targeted single-cell RNA sequencing and multicolor flow cytometry. Results: Two CAR-T infusions were not better than one in the settings used in this study. As for the CAR-T infusion products we found that effector-like CD8+CAR-T cells with a high polyfunctionality, high cytotoxic and cytokine production profile and low dysfunctional signature was associated with clinical response. An extended ex vivo expansion time during CAR-T manufacturing negatively influenced the proportion of effector CD8+CAR-T cell in the infusion product. Conclusions: We identified cell-intrinsic characteristics of effector CD8+CAR-Ts correlating with response that could be used as an indicator for clinical outcome. The results in the study also serves as a guide to CAR-T manufacturing practices.