Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Academic Article uri icon

Overview

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.

publication date

  • August 13, 2018

Research

keywords

  • Programmed Cell Death 1 Receptor
  • Receptors, Chimeric Antigen
  • Single-Chain Antibodies
  • T-Lymphocytes

Identity

PubMed Central ID

  • PMC6126939

Scopus Document Identifier

  • 85053082722

Digital Object Identifier (DOI)

  • 10.1038/nbt.4195

PubMed ID

  • 30102295

Additional Document Info

volume

  • 36

issue

  • 9