Effective Targeting of TAG72+ Peritoneal Ovarian Tumors via Regional Delivery of CAR-Engineered T Cells

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.

Epithelial Ovarian Cancer and the Immune System: Biology, Interactions, Challenges and Potential Advances for Immunotherapy

“…In support of this, a xenograft mouse model of ovarian cancer with CAR-T cells targeting tumour-associated glycoprotein (TAG72), found that i.p. delivery eliminated antigen-positive disease and extended the overall survival of mice, while intravenous CAR-T cell delivery was ineffective in controlling disease [ 346 ]. Further improvements to CAR-T design for solid tumour immunotherapy will be required to overcome immunosuppressive influences from the TME that result in suboptimal CAR-T cell function.…”

“…In combination with hypersialylation found in cancers [ 56 ], O -Linked Tn, Sialyl-Tn and T antigens are produced by incomplete glycosylation of mucins and are characteristic for most carcinomas [ 183 ]. Sialyl-Tn has been identified as tumour-associated glycoprotein 72 (TAG72) and is present in high levels in multiple histological sub-types of ovarian cancer [ 346 ]. The presence of TAG72 has been confirmed on MUC1 and CD44 [ 376 ] (an ovarian cancer stem cell marker and receptor for the ECM molecule hylauronan [ 377 ]) as well as CD133 (a marker present in cancer stem-cells including ovarian cancer) [ 378 ] and MUC16 proteins [ 379 ] in ovarian cancer patients.…”

“…The presence of TAG72 has been confirmed on MUC1 and CD44 [ 376 ] (an ovarian cancer stem cell marker and receptor for the ECM molecule hylauronan [ 377 ]) as well as CD133 (a marker present in cancer stem-cells including ovarian cancer) [ 378 ] and MUC16 proteins [ 379 ] in ovarian cancer patients. CAR-T cells engineered with a CD137 co-stimulatory signaling domain targetting TAG72 have shown cytokine production and cytoxicity against TAG72+ ovarian cancer cell lines and ascites [ 346 ]. In addition, i.p.…”

“…In addition, i.p. delivery of these cells significantly reduced tumour growth and improved overall survival in mice with peritoneal ovarian cancer xenografts [ 346 ].…”

Implantable Therapeutic Reservoir Systems for Diverse Clinical Applications in Large Animal Models

“…Intraperitoneal infusion with CAR T‐cells can also reduce tumor burden in animal models of peritoneal carcinomatosis, [ 18 ] with repeat dosing leading to an improved response. [ 19,20 ] Intramuscular delivery of cells to skeletal muscle has also been used for treatment of critical limb ischemia [ 21–24 ] and skeletal muscle regeneration, [ 25–27 ] obviating the need for localized delivery of cells to intramuscular targets. Cardiac tissue may also benefit from direct cell delivery compared to systemic administration; for example, implantation of stem cells in the heart leads to improved retention [ 28 ] and cardiac function after myocardial infarction via paracrine mediators, [ 11–13 ] and several studies in rodents suggest repeated dosing provides functional improvement compared to a single infusion of cells.…”