Abstract Small cell lung cancer (SCLC), accounting for approximately 15% of all lung cancer cases, represents an aggressive carcinoma characterized by rapid proliferation, early dissemination, and the development of therapeutic resistance. Recent transcriptomic profiling has delineated SCLC into distinct molecular subtypes defined by the expression of lineage-specifying transcription factors ASCL1, NEUROD1, YAP1, and POU2F3. Among these, the neuroendocrine subtypes SCLC-A (ASCL1-driven) and SCLC-N (NEUROD1-driven) predominate in 80% of patient populations. Due to the intrinsically low expression of major histocompatibility complex (MHC) molecules and the consequent poor responsiveness to immune checkpoint blockade, the development of MHC-independent immunotherapeutic strategies is imperative for SCLC. Cell Adhesion Molecule 1 (CADM1), a membrane glycoprotein with context-dependent tumor suppressor and pro-tumorigenic functions, is aberrantly expressed in SCLC and implicated in regulating cellular adhesion, immune evasion, and metastatic dissemination. Our analyses revealed that CADM1 expression inversely correlates with MHC expression scores and is enriched in treatment-naïve tumors with high neuroendocrine differentiation (ASCL1- and NEUROD1-dominant subtypes). The overexpression of CADM1 in tumor cells, makes it an attractive target for antigen-specific immunotherapy. To exploit this vulnerability, we engineered a CADM1-specific chimeric antigen receptor (CADM1-CAR) T cell. CADM1-CAR T cells exhibited robust antigen-dependent cytotoxicity, enhanced secretion of effector cytokines (IFN-γ, TNF-α), and upregulation of cytolytic mediators (granzyme A/B, perforin), resulting in potent SCLC cell lysis in vitro. In NSG mice bearing disseminated H82 xenografts, CADM1-CAR T cell treatment significantly inhibited tumor progression and extended overall survival. These findings establish CADM1 as a promising tumor-associated antigen and support the therapeutic potential of CADM1-targeted CAR T cell therapy for high-grade neuroendocrine SCLC. Citation Format: Shiva Krishna Katkam, Sergei Chuikov, Zhefan Wang, Venkateshwar Keshamouni, . CADM1-CAR T cells targeting neuroendocrine subtypes of small cell lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1536.
Katkam et al. (Fri,) studied this question.