No abstract

The efficacy of chimeric antigen receptor (CAR) T cell therapy against poorly responding tumors can be enhanced by administering the cells in combination with immune checkpoint blockade inhibitors. Alternatively, the CAR construct has been engineered to coexpress factors that boost CAR-T cell function in the tumor microenvironment. We modified CAR-T cells to secrete PD-1-blocking single-chain variable fragments (scFv). These scFv-secreting CAR-T cells acted in both a paracrine and autocrine manner to improve the anti-tumor activity of CAR-T cells and bystander tumor-specific T cells in clinically relevant syngeneic and xenogeneic mouse models of PD-L1 hematologic and solid tumors. The efficacy was similar to or better than that achieved by combination therapy with CAR-T cells and a checkpoint inhibitor. This approach may improve safety, as the secreted scFvs remained localized to the tumor, protecting CAR-T cells from PD-1 inhibition, which could potentially avoid toxicities associated with systemic checkpoint inhibition.

The engineered expression of chimeric antigen receptors (CARs) on the surface of T cells enables the redirection of T-cell specificity. Early clinical trials using CAR T cells for the treatment of patients with cancer showed modest results, but the impressive outcomes of several trials of CD19-targeted CAR T cells in the treatment of patients with B-cell malignancies have generated an increased enthusiasm for this approach. Important lessons have been derived from clinical trials of CD19-specific CAR T cells, and ongoing clinical trials are testing CAR designs directed at novel targets involved in haematological and solid malignancies. In this Review, we discuss these trials and present strategies that can increase the antitumour efficacy and safety of CAR T-cell therapy. Given the fast-moving nature of this field, we only discuss studies with direct translational application currently or soon-to-be tested in the clinical setting.

. planned the research, performed experiments, analyzed data, drafted the first and subsequent drafts of the letter, and approved the final version of the letter; J.P.B. and C.C. were involved in planning components of the research, performing experiments, reviewed drafts, and approved the final version of the letter; X.Z. was involved in planning components of the research, did all the statistical analysis, reviewed drafts, and approved the final version of the letter; J.J.B. provided input and suggestions to the presentation of the data and a critical reagent (ibrutinib) essential for completion of the work, and reviewed and approved the final version of the letter; N.M. and R.L. provided input into experimental design, reviewed drafts of the manuscript, and approved the final submitted version; and A.J.J. and J.C.B. planned every aspect of the proposal, supervised the research, analyzed data, reviewed drafts, obtained funding for the research work, and approved the final version of the letter.