Breast Cancer Brain Metastasis Therapy by Focused Ultrasound-Guided Control of HER2 CAR T cells

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Project Summary HER2-targeted therapies are promising treatment options for metastatic breast cancer and have improved the median overall survival. However, breast cancer brain metastasis (BCBM), which is observed in up to 50% of HER2-positive breast cancer patients, continues to be a clinical challenge with most patients surviving less than 2 years following CNS involvement. These dismal outcomes underscore the need for new and more effective treatments for BCBM. Chimeric Antigen Receptor (CAR) T cell therapy has led to durable responses in patients with certain types of blood cancers. However, the treatment of brain tumors, such as BCBM, involves a unique set of challenges, including limited infiltration of CAR T cells, heterogenous expression of target CAR antigens, and high systemic toxicity. Although direct intracranial administration of CAR T cells has resulted in anti-tumor responses in a few patients with relatively low systemic toxicity, BCBM is multifocal and requires repeat treatments, which pose significant challenges to effective delivery. Moreover, in recent clinical trials, heterogeneous antigen expression led to relapse from the outgrowth of antigen-negative tumor cells. Therefore, new strategies that can concurrently increase CAR T cell infiltration, combat tumor heterogeneity, and limit off target toxicity are necessary to address the critical and unmet need to treat BCBM. Recently advances in Magnetic Resonance guided Focused Ultrasound (MRgFUS) technology and CAR T cell engineering are uniquely suited to advance CAR T cell therapy for difficult-to-treat BCBM. Closed-loop control of MRgFUS enables spatially localized and noninvasive application of mild hyperthermia (41.5 ± 0.5 oC) in the brain across an intact skull that can transiently increase perfusion and vessel permeability in brain tumors. Preliminary studies indicate that FUS-induced hyperthermia also increases trafficking of CAR T cells to brain tumors. In complementary studies, engineered CAR T cells that respond to mild hyperthermia (40–42 oC) by producing a bi-specific T cell engager (BiTE) that targets CD3 and natural killer group 2 member D ligands (NKG2DL) has been shown to potentiate anti-tumor activity and mitigate antigen escape. By merging these synergistic advances in image-guided therapy and CAR T cell engineering, the proposal objective seeks to apply thermal targeting of brain tumors by MRgFUS to enhance therapeutic trafficking of CAR T cells and spatially control the intratumoral production of BiTEs to potentiate anti-tumor responses against BCBM. Preclinical studies will focus on HER2+ BCBM using both syngeneic and human HER2 (hHER2) transgenic mouse models. The proposed grant will refine, integrate, and test using clinically relevant models two exciting technologies that, if successful, can offer desperately needed new treatment strategies to patients with BCBM.