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

项目摘要 HER2靶向疗法是转移性乳腺癌的有希望的治疗选择，并且改善了乳腺癌的预后。 中位总生存期。然而，乳腺癌脑转移（BCBM），这是观察到高达50%的 HER2阳性乳腺癌患者仍然是一个临床挑战，大多数患者的存活率低于 CNS受累后2年。这些令人沮丧的结果强调了需要新的和更有效的 BCBM的治疗嵌合抗原受体（CAR）T细胞疗法已在患者中产生持久反应 某些类型的血癌。然而，脑肿瘤的治疗，如BCBM，涉及一种独特的治疗方法。 一系列挑战，包括CAR T细胞的有限浸润，靶CAR抗原的异源表达， 和高全身毒性。尽管CAR T细胞的直接颅内给药已经导致了抗肿瘤作用， BCBM是多灶性的，需要重复治疗， 治疗，这对有效交付构成重大挑战。此外，在最近的临床试验中， 异质性抗原表达导致抗原阴性肿瘤细胞生长的复发。因此，我们认为， 新的策略，可以同时增加CAR T细胞浸润，对抗肿瘤异质性，并限制肿瘤细胞的生长。 靶向毒性对于解决治疗BCBM的关键和未满足的需求是必要的。最近的进展， 磁共振引导聚焦超声（MRgFUS）技术和CAR T细胞工程是 特别适合于推进CAR T细胞治疗难以治疗的BCBM。MRgFUS的闭环控制 能够在整个大脑中进行空间定位和非侵入性的轻度高温治疗（41.5 ± 0.5 oC）， 一个完整的头骨，可以暂时增加脑肿瘤的灌注和血管通透性。初步研究 表明FUS诱导的高热也增加了CAR T细胞向脑肿瘤的运输。在 补充研究，工程化CAR T细胞通过产生一种 靶向CD3和自然杀伤组2成员D配体（NKG2DL）的双特异性T细胞增殖剂（BiTE）具有 已显示增强抗肿瘤活性并减轻抗原逃逸。通过整合这些协同进步 在图像引导治疗和CAR T细胞工程中，该提案的目标是将热靶向应用于 通过MRgFUS增强CAR T细胞的治疗性运输并在空间上控制肿瘤内 产生BiTE以增强针对BCBM的抗肿瘤应答。临床前研究将重点关注HER2+ 使用同基因和人HER2（hHER2）转基因小鼠模型的BCBM。拟议的赠款将 使用临床相关模型完善、整合和测试两项激动人心的技术，如果成功， BCBM患者迫切需要新的治疗策略。

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.