Abstract
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.
Highlights
Chimeric antigen receptor (CAR)-engineered T cell therapy in patients with CD19+ B-cell malignancies have demonstrated impressive clinical responses [1, 2], which recently resulted in two landmark FDA approvals for patients with leukemia and lymphoma
Using in vivo peritoneal ovarian tumor models, we show that regional intraperitoneal delivery of tumor-associated glycoprotein 72 antigen (TAG72)-BBζ chimeric antigen receptor (CAR) T cells eliminate antigen-positive disease and extends overall survival of mice, while intravenous CAR T cell delivery was ineffective in controlling disease
Our first goal was to develop a second-generation TAG72-BBζ CAR construct containing the humanized scFv CC49, the human IgG4 Fc extracellular spacer lacking a CH2 domain ( CH2), the CD4 transmembrane domain, the 4-1BB intracellular costimulatory domain, and the CD3ζ cytolytic domain followed by a truncated CD19 (CD19t) for cell tracking (Figure 1A)
Summary
Chimeric antigen receptor (CAR)-engineered T cell therapy in patients with CD19+ B-cell malignancies have demonstrated impressive clinical responses [1, 2], which recently resulted in two landmark FDA approvals for patients with leukemia and lymphoma. These studies have shown that CAR T cells can be optimized to induce durable and complete responses in cancer patients, even under conditions of highly refractory disease. Multiple cancer types including colon, breast, pancreas, and ovarian, are known to over-express aberrantly glycosylated proteins, including the mucins MUC16 and MUC1, and the tumor-associated glycoprotein 72 antigen (TAG72) [9], that differentiate them from normal epithelia. Approximately 90% of epithelial ovarian cancers are TAG72 positive, indicating its abundance across multiple histological subtypes of ovarian cancer [11]
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