%0 Generic %A Murad, John P. %A Kozlowska, Anna K. %A Lee, Hee Jun %A Ramamurthy, Maya %A Chang, Wen-Chung %A Yazaki, Paul %A Colcher, David %A Shively, John %A Cristea, Mihaela %A J. Forman, Stephen %A J. Priceman, Saul %D 2018 %T Data_Sheet_1_Effective Targeting of TAG72+ Peritoneal Ovarian Tumors via Regional Delivery of CAR-Engineered T Cells.PDF %U https://frontiersin.figshare.com/articles/dataset/Data_Sheet_1_Effective_Targeting_of_TAG72_Peritoneal_Ovarian_Tumors_via_Regional_Delivery_of_CAR-Engineered_T_Cells_PDF/7359131 %R 10.3389/fimmu.2018.02268.s001 %2 https://frontiersin.figshare.com/ndownloader/files/13598987 %K chimeric antigen receptor %K ovarian cancer %K regional intraperitoneal delivery %K TAG72 %K tumor-associated glycoproteins %K adoptive cellular immunotherapy %K STn %K sialyl-Tn %X

Impressive clinical efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy for hematological malignancies have prompted significant efforts in achieving similar responses in solid tumors. The lack of truly restricted and uniform expression of tumor-associated antigens, as well as limited T cell persistence and/or tumor trafficking pose major challenges for successful translation of CAR T cell therapy in solid tumors. Recent studies have demonstrated that aberrantly glycosylated cell surface proteins on tumor cells are amenable CAR targets. Tumor-associated glycoprotein 72 (TAG72) antigen is the sialyl-Tn found on multiple O-glycoproteins expressed at high levels on the surface of several cancer types, including ovarian cancer. Here, we developed a humanized TAG72-specific CAR containing a 4-1BB intracellular co-stimulatory signaling domain (TAG72-BBζ). TAG72-BBζ CAR T cells showed potent antigen-dependent cytotoxicity and cytokine production against multiple TAG72+ ovarian cancer cell lines and patient-derived ovarian cancer ascites. Using in vivo xenograft models of peritoneal ovarian tumors, regional intraperitoneal delivery of TAG72-BBζ CAR T cells significantly reduced tumor growth, extended overall survival of mice, and was further improved with repeat infusions of CAR T cells. However, reduced TAG72 expression was observed in early recurring tumors, which coincided with a lack of T cell persistence. Taken together, we demonstrate efficacy with TAG72-CAR T cells in ovarian cancer, warranting further investigations as a CAR T cell therapeutic strategy for this disease.

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