Abstract 3527: Low-intensity pulsed focused ultrasound, with microbubbles and immune adjuvants, promotes CNS epitope spreading, improving CAR T cell therapy for heterogeneous brain tumors

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Abstract While chimeric antigen receptor (CAR) T-cell therapies present novel therapeutic opportunities, their clinical success has been limited when targeting malignant brain tumors, such as malignant gliomas. Marked antigenic heterogeneity of those tumors underlies their treatment resistance. Ultimately, it is crucial to promote endogenous T cell responses against tumor cells not targeted by the CAR (“epitope-spreading”). However, natural anatomical barriers and an immunosuppressive environment allow neoplasms within the brain to evade detection by the endogenous immune system. We identified that low-intensity pulsed focused ultrasound combined with microbubbles (LIPU/MB)-mediated transient blood-brain barrier (BBB) opening enables the trafficking of antigen-presenting cells from the central nervous system (CNS) into the periphery utilizing intravital two-photon microscopy, multiparametric spectral flow cytometry, bone marrow chimera mice and blood samples from glioblastoma patients treated with LIPU/MB. Because mouse glioma models do not allow us to study the immune response with the intact BBB, we created a novel transgenic mouse model in which MHC class I- or II-presented T-cell epitopes are restrictedly expressed in glial cells. A combination of LIPU/MB with immune adjuvants poly-ICLC and interleukin-2 promoted priming, activation and homing of CNS-antigen-specific naïve T cells into the brain. Genetic depletion of β2 microglobulin in systemic hematopoietic cells by bone marrow chimera showed that this phenomenon was independent of antigen presentation by peripheral bone marrow-derived cells. Furthermore, T cell activity in the brain also induced MHC-I and MHC-II epitope spreading, shown as significantly increased endogenous epitope-specific T cells in the deep cervical lymph nodes and spleen. Ultimately, the combination of LIPU/MB with poly-ICLC and IL-2 significantly enhanced the efficacy of EGFRvIII CAR T cell therapy in mice harboring heterogenous (CAR+ and CAR-) SB28 tumors. Therapeutic efficacy was associated with the presence of endogenous immune cells targeting other tumor antigens within the CNS. Collectively, our findings suggest that LIPU/MB, in combination with poly-ICLC and Interleukin-2, can overcome the inherent limitations of CAR T cell therapy by promoting CNS antigen presentation to the peripheral immune system inducing endogenous tumor-tumor-specific immune responses that enhance the efficacy of CAR T cell therapy. Citation Format: Marco Gallus, Akane Yamamichi, Victor Andres. Arrieta, Atsuro Saijo, Lan Phung, Pavlina Chuntova, Su Phyu, Jeffrey Haegelin, Aishi Zhao, Haoyu Long, Senthilnath Lakshmanachetty, Takahide Nejo, Kaori Okada, Li Chen, Karl Habashy, Andrew Gould, Christina Amidei, Catalina Lee Chang, Roger Stupp, Michael Canney, Adam M. Sonabend, Hideho Okada. Low-intensity pulsed focused ultrasound, with microbubbles and immune adjuvants, promotes CNS epitope spreading, improving CAR T cell therapy for heterogeneous brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3527.

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