Abstract 2364: Anti-CADM1 chimeric antigen receptor (CAR) is a novel therapeutic strategy against small cell lung cancer

Abstract

Abstract Small cell lung cancer (SCLC) is a highly aggressive form accounting for 15% of all lung cancers. SCLC is characterized by high proliferative rates, early metastasis, and poor prognosis. The median survival is less than 2 years even in patients with early-stage disease and less than a year in patients with metastatic disease which highlights the need for new therapeutic strategies. Cell Adhesion Molecule (CADM) 1 encodes a glycoprotein which belongs to an immunoglobulin superfamily of cell adhesion molecules responsible for epithelial cell adhesion through its homophilic trans-interaction between the adjacent cells. CADM1 is highly expressed on the cell surface of 80% of the SCLC cells, associated with its neuroendocrine features, along with the expression of Neural Cell Adhesion Molecule (NCAM). CADM1 is known to act as tumor promoter through its interactions with actin binding proteins. Consistently, we observed CADM1 expression in H69, H82, and H510 SCLC cell lines as assessed by western immuno blot. More importantly they were all susceptible to NK mediated cytotoxicity when assessed against NK cell line, NK92. We previously demonstrated that CADM1 mediates NK-mediated immune surveillance in non-small cell lung cancer, suggesting that CADM1 could be a potential immunotherapeutic target for SCLC. Here we report the development of an anti-CADM1 chimeric antigen receptor (CAR) specific for T and NK cells engineered with T and NK cell specific adaptor domains. Assessed the specificity of CARs by expressing them in NK92 cells and testing them against CADM1 expressing and CADM1-null A549 cells as targets. Finally, we evaluated the efficacy of anti-CADM1 CAR-T and CAR-NK cells against SCLC targets and observed a robust killing, largely proportionate to the levels of CADM1 expression in them. We are further assessing the efficacy of anti-CADM1 CAR-T and CAR-NK products in inhibiting tumor growth in NSG mice against SCLC xenografts. Together, these observations demonstrate that targeting CADM1 with CAR-T and CAR-NK cells is a potential new therapeutic strategy for SCLC. Citation Format: Shiva Krishna Katkam, Sergei Zolov, Delaney Shield, Sergei Chuikov, Venkateshwar G Keshamouni. Anti-CADM1 chimeric antigen receptor (CAR) is a novel therapeutic strategy against small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2364.