Regression of established renal cell carcinoma in nude mice using lentivirus-transduced human T cells expressing a human anti-CAIX chimeric antigen receptor

• DOI: 10.1038/mto.2014.3
• Publication Date: 2014-12-08T20:12:48Z
• Authors: Agnes Shuk-Yee Lo; Chen Xu; Akikazu Murakami; Wayne A Marasco
• Keywords: 0301 basic medicine; 03 medical and health sciences; 610; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; RC254-282; Article; 3. Good health

Carbonic anhydrase IX (CAIX) is a tumor-associated antigen and marker of hypoxia that is overexpressed on > 90% of clear-cell type renal cell carcinoma (RCC) but not on neighboring normal kidney tissue. Here, we report on the construction of two chimeric antigen receptors (CARs) that utilize a carbonic anhydrase (CA) domain mapped, human single chain antibody (scFv G36) as a targeting moiety but differ in their capacity to provide costimulatory signaling for optimal T cell proliferation and tumor cell killing. The resulting anti-CAIX CARs were expressed on human primary T cells via lentivirus transduction. CAR-transduced T cells (CART cells) expressing second-generation G36-CD28-TCRζ exhibited more potent in vitro antitumor effects on CAIX(+) RCC cells than first-generation G36-CD8-TCRζ including cytotoxicity, cytokine secretion, proliferation, and clonal expansion. Adoptive G36-CD28-TCRζ CART cell therapy combined with high-dose interleukin (IL)-2 injection also lead to superior regression of established RCC in nude mice with evidence of tumor cell apoptosis and tissue necrosis. These results suggest that the fully human G36-CD28-TCRζ CARs should provide substantial improvements over first-generation mouse anti-CAIX CARs in clinical use through reduced human anti-mouse antibody responses against the targeting scFv and administration of lower doses of T cells during CART cell therapy of CAIX(+) RCC.