Abstract 1332: Selective targeting of the α3β4 nicotinic acetylcholine receptor by DISCO (dual interacting subunit complex) CAR T cells.

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Abstract Developing effective chimeric antigen receptor (CAR) T cell therapies for pediatric solid tumors requires discovery of highly tumor-selective cell surface molecules. Using a multimodal immunotherapeutic target discovery platform, we identified a receptor composed of the nicotinic acetylcholine receptor subunits α3 and β4 as a new previously unrecognized immunotherapeutic target in neuroblastoma. CHRNA3 (α3) and CHRNB4 (β4) are robustly differentially overexpressed in neuroblastoma compared with normal tissues, driven by a super-enhancer upstream of the CHRNA3/B4 locus on chromosome 15q25 that is occupied by neuroblastoma core regulatory transcription factors and physically engages both promoters. Neuroblastoma cells exhibit abundant α3 and β4 protein, which bind and assemble into a stabilized α3β4 complex displayed at high levels on the neuroblastoma cell surface. Functionally, genetic depletion of α3 also reduced β4 levels, induced mesenchymal cell state-associated marker expression, and increased proliferation and invasion in neuroblastoma cell line models. To therapeutically exploit this tumor-restricted α3β4 receptor expression, we engineered Dual Interacting Subunit COmplex (DISCO)-specific single chain variable fragments (scFvs) designed to recognize an epitope requiring simultaneous engagement of both α3 and β4 subunits of the α3β4 cell surface receptor. DISCO CAR T cells generated from these scFvs bound selectively to and were potently activated by the α3β4 receptor, but not either subunit individually. α3β4-targeted DISCO CAR T cells demonstrated potent and selective cytotoxicity across diverse neuroblastoma cell lines and three patient-derived xenograft (PDXs) models, significantly extending the survival of mice harboring PDXs with a range of α3 and β4 expression (P < 0.05). Beyond neuroblastoma, CHRNA3 and CHRNB4 are also highly expressed in small cell lung cancer (SCLC) and retinoblastoma, among several other tumors. The identical super-enhancer is associated with high levels of CHRNA3 and CHRNB4 in SCLC, suggesting similar mechanisms of tumor-driven overexpression. In an intraocular retinoblastoma xenograft model, a single intravitreal dose of α3β4-redirected DISCO CAR T cells achieved marked tumor control and significantly extended ocular survival (P = 0.0015), collectively showing disease-relevance and targetability beyond neuroblastoma. Together, these findings broaden the repertoire of actionable CAR T cell targets in pediatric and adult solid tumors by validating the α3β4 receptor, and more broadly the nicotinic acetylcholine receptor family, as bona fide immunotherapeutic candidates. Moreover, these studies demonstrate that CARs can be designed to recognize disease-relevant subunit configurations within multidomain surface receptors. Citation Format: Patrick M. Schürch, Vincent P. Zecchino, Anna M. Giudice, Rebecca S. Kaufman, Evan Cresswell-Clay, Guillem Pascual-Pasto, Sydney L. Roth, Brendan C. McIntyre, Rawan Shraim, Amber K. Hamilton, Kush Parikh, Karina L. Conkrite, Khanh B. Trang, Grant P. Grothusen, David Groff, Pamela Mishra, Simona Lombardi, Tyler Skinner, Andrew D. Wells, Struan F. Grant, Daniel Martinez, Wei Li, Sharon J. Diskin, Kristopher R. Bosse. Selective targeting of the α3β4 nicotinic acetylcholine receptor by DISCO (dual interacting subunit complex) CAR T cells [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 1332.

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