Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo

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.

Improved survival of chimeric antigen receptor‐engineered T (CAR‐T) and tumor‐specific T cells caused by anti‐programmed cell death protein 1 single‐chain variable fragment‐producing CAR‐T cells

“…As we recently reported, synergistic effects with endogenous tumor‐specific T cells are essential to optimize the therapeutic potential of CAR‐T cells against solid tumors. In this regard, three recent studies reported CAR‐T cells engineered to produce soluble PD‐1 blockers . Among these studies, two of them used NSG immune‐deficient mice as recipients, so that effects on endogenous tumor‐specific T cells could not be evaluated .…”

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…To remedy to this, Caruana et al engineered T cells to secrete heparanase enabling the efficient degradation of ECM and targeting of neuroblastoma tumors in mouse [258]. Furthermore, it is feasible to engineer T cells to secrete checkpoint blockers [259][260][261] (Fig. 1) or HVEM [262] to lower the immunosuppressive pressure in the tumor vicinity.…”

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

“…Some groups are also exploring the possibility of combing CAR T cells with oncolytic viruses (124) or with checkpoint inhibitors (125)(126)(127). Indeed, targeting the PD-1/PD-L1 axis is of particular interest for CAR-T cells development in solid tumors (128), and investigators are testing constructs which are able to deliver anti-PD-1 molecules (129,130) and strategies of cell-intrinsic PD-1 inhibition and inactivation (126,131,132), with the aim of improving the efficacy of CAR T cells also reducing the systemic side effects of checkpoint inhibitors.…”