Abstract 5505: ADAM10-targeting CAR-T cells inhibit colon cancer cell growth in vivo

Abstract

Abstract Chimeric antigen receptor (CAR) T cell therapy has demonstrated a high degree of efficacy in patients with hematological malignancies such as acute lymphatic leukemia. However, its efficacy in solid tumors remains to be demonstrated. There are a number of issues currently limiting therapeutic treatment of solid tumors with CAR-T cells, none more important than target antigen selection. This is a major challenge in solid tumors due to their heterogenous characteristics and the potential for off-cancer effects. ADAM10, A Disintegrin And Metalloproteinase 10, plays critical roles in a wide range of pathophysiological processes during development and inflammation. These proteolytically active multifunctional proteins act as sheddases by cleaving transmembrane-bound proteins such as growth factors, adhesion molecules and chemokine receptors, which can then contribute to migration and invasion of cancer cells. An active form of ADAM10 that has undergone a conformational change has been identified in several cancer types, particularly colorectal cancer. In this study, a novel CAR was generated based on a previously characterized cancer-specific ADAM10 antibody. ADAM-10-targeting CAR-T cells were manufactured using T cells from the peripheral blood of the healthy donors. The CAR-T cells displayed the naïve and central memory phenotype that has been shown to differentiate and proliferate within tumor microenvironments, with little expression of exhaustion markers. These CAR-T cells were capable of killing several human colorectal tumor cell lines in vitro, assessed in a bioluminescence-based cytotoxicity assay. Furthermore, treatment of NSG mice bearing human LoVo colon cancer cell tumors with ADAM-10-targeting CAR-T cells led to significant inhibition of tumor growth compared with either untransduced control T cells or PBS treatment. Overall, these data suggest that targeting ADAM-10 via CAR-T cell therapy is a promising novel avenue of treatment of colorectal cancer. Citation Format: Elaheh Rohani Rad, Jade Foeng, Dylan McPeak, Timona Tyllis, Caitlin Abbott, Veronika bandara, Silvana Napoli, Batjargal gundsambuu, Simon Barry, Timothy Sadlon, shaun McColl. ADAM10-targeting CAR-T cells inhibit colon cancer cell growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5505.