Abstract A032: Efficacy of nuclear envelope protein targeting CAR T cell therapy for MYC driven group 3 medulloblastoma

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Abstract Medulloblastoma (MB) is the most common, malignant pediatric brain tumour comprised of four distinct molecular subgroups (WNT, SHH, Group 3, and Group 4). A subset of Group 3 MB tumors harbor focal amplifications of the MYC oncogene (MYC-G3MB) that are prone to leptomeningeal spread and recurrence which remains incurable. Therefore, there is an urgent need for the development of therapeutic modalities that are safe and have potent antitumour efficacy against recurrent MB. We discovered that nuclear envelope (NE) proteins LBR and TMPO are aberrantly presented to the cell surface in MYC-G3MB cell lines with little to no expression in normal cells. We identified that positive LBR staining in MB patient samples correlated with a significantly worse prognosis and was also enriched in recurrent tissue compared to their matched primary samples. High resolution microscopy of endogenously tagged HALO-LBR and mNeon-TMPO reveals cell surface presentation to be linked to ER or ER-like vesicles that are trafficked and accumulated at the cell surface. Transcriptomic analysis of LBR cell surface positive and negative cells identified that cell surface positivity is significantly linked to cell division and mitotic processes. Tracking of LBR and TMPO expression across embryonal development identify expression to be significantly linked to prenatal development that dampens postnatally. To generate NE-specific CAR T cell therapies that would target these hyper proliferative specific G3MB subpopulations we engineered single domain antibodies (sdAb) against the N-termini of LBR and TMPO. NE protein targeting CAR T cell therapies revealed potent antitumour efficacy against MYC-G3MB cells both in vivo and in vitro. We present a novel class of therapeutic targets that define a mechanistically distinct therapy-resistant population for potential translation into early phase clinical trials. Citation Format: Yujin Suk, Jorge Ibañez-Vega, Martin Rossotti, Vaseem Shaikh, Yiyun Chen, Hardikkumar Patel, Laura Escudero, Alberto Delaidelli, Sarah Slassi, Carlos B. Bazan, Aapti Khanna, Sumayyah Sokeechand, Erika Apel, Iqra Chaudhry, Stefan Custers, Shan Grewal, Mohamed Taleb, Takuma Nakashima, William Maich, Lucas Asselstine, Dillon McKenna, Minomi Subapanditha, Petar Miletic, Yuxi Xiao, William D. Gwynne, Jason Moffat, Hiromichi Suzuki, Poul Sorensen, Ray Truant, Kevin A. Henry, Elena Sotillo, Chitra Venugopal, Crystal Mackall, Giedre Krenciute, Sheila K. Singh. Efficacy of nuclear envelope protein targeting CAR T cell therapy for MYC driven group 3 medulloblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A032.

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