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 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.
authors.forename: Leonid
authors.initials: L
authors.lastname: Cherkassky
authors.forename: Aurore
authors.initials: A
authors.lastname: Morello
authors.forename: Jonathan
authors.initials: J
authors.lastname: Villena-Vargas
authors.forename: Yang
authors.initials: Y
authors.lastname: Feng
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
authors.forename: Prasad S
authors.initials: PS
authors.lastname: Adusumilli
mesh_terms: D016475:3T3 Cells; D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D000090204:Mesothelin; D008654:Mesothelioma / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local; D010997:Pleural Neoplasms / Q000276:immunology / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018106:CD28 Antigens; D016207:Cytokines; C000715528:Msln protein, mouse; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D000090204:Mesothelin