期刊
SCIENTIFIC REPORTS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-10940-8
关键词
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资金
- National Institutes of Health [R01CA138738-05, PO1CA059350, PO1CA190174-01]
- Memorial Sloan Kettering T32 Investigational Therapeutics Training Program [T32-CA009207]
- Annual Terry Fox Run for Cancer Research (New York, NY) [29410]
- Kate's Team, Carson Family Charitable Trust [10171]
- William Lawrence and Blanche Hughes Foundation [10251]
- Emerald Foundation [11625]
- Conquer Cancer Foundation ASCO Young investigator award [229186]
- Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center [13072]
Chimeric antigen receptor (CAR) T cell therapy has shown limited efficacy for the management of solid tumor malignancies. In ovarian cancer, this is in part due to an immunosuppressive cytokine and cellular tumor microenvironment which suppresses adoptively transferred T cells. We engineered an armored CAR T cell capable of constitutive secretion of IL-12, and delineate the mechanisms via which these CAR T cells overcome a hostile tumor microenvironment. In this report, we demonstrate enhanced proliferation, decreased apoptosis and increased cytotoxicity in the presence of immunosuppressive ascites. In vivo, we show enhanced expansion and CAR T cell antitumor efficacy, culminating in improvement in survival in a syngeneic model of ovarian peritoneal carcinomatosis. Armored CAR T cells mediated depletion of tumor associated macrophages and resisted endogenous PD-L1-induced inhibition. These findings highlight the role of the inhibitory microenvironment and how CAR T cells can be further engineered to maintain efficacy.
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