Regression of established renal cell carcinoma in nude mice using lentivirus-transduced human T cells expressing a human anti-CAIX chimeric antigen receptor.
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.
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Agnes Shuk-Yee
AS
Lo
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Beijing Tri-Prime Genetic Engineering Co., Ltd, Beijing, P.R. China.
Chen
C
Xu
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Department of Parasitology & Immunopathoetiology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
Akikazu
A
Murakami
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Wayne A
WA
Marasco