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


Authors: Cherkassky, L.; Morello, A.; Villena-Vargas, J.; Feng, Y.; Dimitrov, D. S.; Jones, D. R.; Sadelain, M.; Adusumilli, P. S.
Article Title: Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition
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 mesothelintargeted 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.
Journal Title: Journal of Clinical Investigation
Volume: 126
Issue: 8
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2016-08-01
Start Page: 3130
End Page: 3144
Language: English
DOI: 10.1172/jci83092
PROVIDER: scopus
PMCID: PMC4966328
PUBMED: 27454297
DOI/URL:
Notes: Article -- Export Date: 3 October 2016 -- Source: Scopus
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MSK Authors
  1. Michel W J Sadelain
    519 Sadelain
  2. David Randolph Jones
    272 Jones
  3. Aurore Ornella Lauriane Morello
    13 Morello