Mechano-Sensing CAR-T Cells for Solid Tumor Metastases

项目概要/摘要：实体瘤转移的长期生存率极低，目前 导致了超过90%的癌症死亡最近，携带工程嵌合抗原受体的T细胞， （CAR-T细胞）在治疗血液癌症方面显示出巨大的前景，但仍面临巨大的挑战。 治疗实体癌的挑战。特别是 由于大多数肿瘤抗原的低水平系统表达， 传统的CAR-T可以在非肿瘤部位被激活，导致主要的“靶向/非肿瘤”侧- 影响 （OTOT）。在这项工作中，我们提出增加CAR-T靶向效率和对实体瘤的特异性， 通过以情境依赖性方式激活CAR-T细胞来减少OTOT副作用。最近的研究 已经证明了癌症微环境的机械特性，包括硬度， 因此，我们假设， 转移性小生境为机械传感CAR-T的开发提供了一个有趣的靶点， 靶向实体瘤及其转移。通过偶联CAR表达（例如，乳腺抗HER 2汽车 癌症）的机械敏感性启动子，我们希望触发T细胞活化，特别是在刚度- 与乳腺癌转移有关。 特定肿瘤微环境。靶向癌抗原和肿瘤生物物理微环境 提示将显著降低“靶向/非肿瘤”副作用，并允许增加T细胞剂量 和功效，共同导致改善的患者结果。该项目将涉及1）建造和 表征在体外特异性响应刚度的CAR-T，以及2）验证机械- 感测CAR-T在体内坚硬肿瘤微环境中特异性激活以治疗乳腺癌肺 拟议的研究可能会导致下一代CAR-T疗法， 转移这 用于治疗转移性乳腺癌和潜在的任何类型的 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.