Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition
Memorial Sloan Kettering Cancer Center
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…
Citation impact
- FWCI
- 39.46
- Percentile
- 100%
- References
- 76
Authors
8Topics & keywords
- CD28
- Cytotoxic T cell
- Chimeric antigen receptor
- T cell
- Cancer research
- Tumor microenvironment
- Immune checkpoint
- Immunotherapy
- Good health and well-being
Funding
- UDU.S. Department of DefenseAwards: BC132124, PR101053, LC110202, P30 CA008748
- AAAmerican Association for Cancer Research
- CRCancer Research InstituteAwards: SU2C-AACR-DT1012, P30 CA008748
- CFCommonwealth Foundation
- ACAmerican College of Surgeons
- EIEntertainment Industry Foundation
- MSMemorial Sloan-Kettering Cancer CenterAward: CA008748
- DFDerfner Foundation
- NINational Institutes of HealthAwards: P30 CA008748, BC132124, SU2C-AACR-DT1012, P50 CA086438-13
- SUStand Up To CancerAward: SU2C-AACR-DT1012
- NCNational Cancer InstituteAwards: CA008748, P30 CA008748, P50 CA086438