Mechano-Sensing CAR-T Cells for Solid Tumor Metastases

项目摘要/摘要：实体肿瘤转移的长期存活率极低，目前 造成了超过90%的癌症死亡。最近，携带工程化嵌合抗原受体的T细胞 (CAR-T细胞)在治疗血液病方面显示出巨大的希望，但仍然面临着巨大的 治疗实体癌症的挑战。特别是 ，由于大多数肿瘤抗原的系统表达水平较低， 传统的CAR-T可以在非肿瘤部位被激活，导致主要的“靶上/肿瘤外”侧- 效果 (OTOT)。在这项工作中，我们建议提高CAR-T对实体瘤的靶向效率和特异性 通过以上下文依赖的方式激活CAR-T细胞来减少OTOT副作用。最新研究 已经证明了癌症微环境的力学性质，包括紧密的刚性 因此，我们假设材料的独特力学性能 转移的生态位为机械传感CAR-T的发展提供了一个有趣的目标，特别是 靶向实体肿瘤及其转移。通过偶联CAR表达(例如，用于乳房的抗HER2 CARS 癌症)到机械敏感启动子，我们希望在僵硬中专门触发T细胞激活- 与乳腺癌转移有关。 特定的肿瘤微环境。靶向肿瘤抗原和肿瘤生物物理微环境 CUES将显著减少靶向/肿瘤外的副作用，并允许增加T细胞剂量 和疗效，共同改善患者的预后。该项目将涉及1)建设和 表征对体外僵硬有特异性反应的汽车，以及2)验证机械-机械系统的有效性。 体内僵硬肿瘤微环境特异性激活传感Car-ts治疗乳腺癌肺癌 拟议的研究可能会导致新一代CAR-T疗法的出现，这种疗法具有独特的靶向 转移瘤。这 转移性乳腺癌和潜在的任何类型乳腺癌转移的机制 实体癌转移。

Project Summary/Abstract: Solid tumor metastasis has extremely low long-term survival rate and is currently responsible for over 90% of cancer deaths. Recently, T cells bearing engineered chimeric antigen receptors (CAR-T cells) have showed tremendous promise in treating hematological cancers but still face tremendous challenges in treating solid cancers. In particular , due to low-level systemic expression of most tumor antigens, conventional CAR-T can be activated at non-tumor sites leading to major “on-target/off-tumor' side- effects (OTOT). In this work we propose to increase CAR-T targeting efficiency and specificity for solid tumors and decrease the OTOT side-effects by activating CAR-T cells in a context-dependent manner. Recent studies have demonstrated that the mechanical properties of cancer microenvironments including stiffness tightly Therefore, we hypothesize that the unique mechanical properties of the metastatic niche offer an intriguing target for the development of mechanosensing CAR-T that specifically target solid tumors and their metastases. By coupling CAR expression (e.g., anti-HER2 CARs for breast cancer) to mechano-sensitive promoters, we expect to trigger T cell activation specifically in the stiffness- correlate to breast cancer metastasis. specific tumor microenvironment. Targeting both cancer antigens AND tumor biophysical microenvironmental cues would significantly reduce the `on target/off tumor' side-effects, and allow for increased T cell dosages and efficacy, collectively leading to improved patient outcomes. This project will involve 1) constructing and characterizing CAR-Ts that specifically respond to stiffness in vitro, and 2) validating whether mechano- sensing CAR-Ts specifically activate in stiff tumor microenvironment in vivo to treat breast cancer lung proposed study could potentially lead to next generation CAR-T therapies that uniquely target metastases. This the mechano-niche of metastases for the treatment of metastatic breast cancer and potentially any types of solid cancer metastasis.