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Cited by 1,074

The DOI matches its Crossref record; 70 of the 70 references it cites were found in a registry or an index.

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

Open access
Cherkassky, Leonid, Morello, Aurore, Villena-Vargas, Jonathan, Feng, Yang, Dimitrov, Dimiter S., Jones, David R., Sadelain, Michel, Adusumilli, Prasad S.·2016·Journal of Clinical Investigation
DOI 10.1172/jci83092
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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.

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Metadata

Authors
Cherkassky, L., Morello, A., Villena-Vargas, J., Feng, Y., Dimitrov, D. S., Jones, D. R., Sadelain, M., & Adusumilli, P. S.
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2016-07-25
Volume
126
Issue
8
Pages
3130-3144
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci83092
OpenAlex
W2504729294
Cited by
1,074
References
70
FWCI
38.63
Type
journal article
Language
en
Open access
bronze

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CoChat. (2026). Citation check: Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. https://app.cochat.ai/papers/10.1172/jci83092
The paper
Cherkassky, L., Morello, A., Villena-Vargas, J., Feng, Y., Dimitrov, D. S., Jones, D. R., Sadelain, M., & Adusumilli, P. S. (2016). Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. Journal of Clinical Investigation. https://doi.org/10.1172/jci83092

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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.