Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition

J Clin Invest. 2016 Aug 1;126(8):3130-44. doi: 10.1172/JCI83092. Epub 2016 Jul 25.

Abstract

Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1-mediated (PD-1-mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB-based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • CD28 Antigens / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cytokines / metabolism
  • Female
  • Genes, Dominant
  • Humans
  • Mesothelioma / metabolism*
  • Mice
  • Mice, Nude
  • Mice, SCID
  • Neoplasm Recurrence, Local
  • Pleural Neoplasms / immunology
  • Pleural Neoplasms / metabolism*
  • Programmed Cell Death 1 Receptor / metabolism*
  • Receptors, Antigen, T-Cell / metabolism*
  • T-Lymphocytes / immunology*

Substances

  • CD28 Antigens
  • Cytokines
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell