Mechanoimmunological interactions between TCR-T cells and tumor fibrotic microenvironment

TCR-T细胞与肿瘤纤维化微环境之间的机械免疫相互作用

• 批准号: 10660424
• 负责人: Richard C Koya
• 金额: $ 61.05万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-09 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660424
• 关键词: Adoptive Cell Transfers; Biomedical Engineering; CAR T cell therapy; CTAG1 gene; Cancer Model; Cell physiology; Cells; Cellular Structures; Chemotactic Factors; Clinical; Clinical Research; Clinical Trials; Collagen; Combined Modality Therapy; Complex; Development; Disease; Extracellular Matrix; FDA approved; Fibroblasts; Fibrosis; Funding; Future; Hematologic Neoplasms; Hematopoietic; Immune; Immunologics; Immunotherapy; In Vitro; Malignant Neoplasms; Malignant neoplasm of ovary; Mechanics; Medical; Modality; Modeling; Mus; Pathogenesis; Pharmaceutical Preparations; Physiological; Pilot Projects; Research; Scientist; Signal Transduction; Solid Neoplasm; T cell response; T cell therapy; T-Cell Receptor; T-Lymphocyte; Testing; Time; Transforming Growth Factor beta; Transgenic Organisms; Treatment Efficacy; Tumor Antigens; Tumor-associated macrophages; United States National Institutes of Health; cancer immunotherapy; cancer therapy; chimeric antigen receptor; clinical efficacy; clinical investigation; density; design; drug development; efficacy testing; engineered T cells; force sensor; improved; innovation; insight; member; microphysiology system; next generation; novel; ovarian neoplasm; success; targeted treatment; therapeutic evaluation; therapeutic target; tool; tumor; tumor-immune system interactions

Adoptive cellular therapies (ACT), including the two modalities: Engineered T Cell Receptor (TCR) Therapy and Chimeric Antigen Receptor (CAR) T Cell Therapy, are currently at the forefront of cancer immunotherapy. While CAR-T therapies has gained clinical success in the treatment of hemopoietic cancers and are approved by FDA, the clinical efficacy for treatment of solid tumors has not been confirmed. In contrast, TCR-T Cell therapies seem more promising for solid tumors, though a main barrier is the disarmament and suppression of the engineered T cells by the fibrotic tumor stroma that contains stiff and structurally-complex extracellular matrix (ECM), cancer associated fibroblasts (CAFs) and various immune cells such as tumor associated macrophages (TAMs). With intensive ongoing clinical investigations on the TCR-T cell therapies that outnumbers the studies on CAR-T therapy, there is an urgent need to understand the mechanism of interaction between TCR-T cells and the tumor stroma. The objective of this project is to dissect and understand the mechano-immunological interaction between TCR-T cells and the fibrotic tumor stroma for improved TCR-T cell immunotherapies. The main hypothesis is that the anti-fibrosis strategies can reduce tumor-associated fibrosis and enhance the ability of TCR-T cells to overcome the immunosuppressive microenvironment, thus leading to improved therapeutic efficacy. The research team consists of a medical scientist who pioneered a two-pronged TCR-T cell therapy (super T cell) that targets tumor antigen NY-ESO-1 and blocks immunosuppressive TGF-β signaling at the same time and is under clinical trials funded by NIH and DoD. The second team member is a biomedical engineer who is specialized in the organotypic modeling of fibrotic diseases and anti-fibrosis drug development. In the current study, novel microphysiological tumor stroma niche models will be developed to investigate the interaction between TCR-T cells and the fibrotic stromal factors with and without the combination of anti-fibrosis therapies. The aims include investigating the competing effect of fibrotic factors on the TCR-T cells to determine the dominant fibrotic factors that suppress the TCR-T cell functions, modeling the dynamic fibrosis progression in the tumor stroma and investigate the different effect of fibrosis inhibition, degradation and blockade on the functions of the TCR-T cells and investigating the mechanism and efficacy of combined anti-fibrosis therapy and TCR-T cell therapy. This project is innovative because the study to dissect the mechanism by which tumor fibrotic stroma suppresses the transgenic TCR-T cells will help to identify the therapeutic targets for the design and optimization of future fibrosis-targeting T cell therapies. The comparison between NY-ESO-TCR-T and Super T cells will directly benefit our ongoing clinical study and help with the evaluation of these therapeutic T cells. It is expected that the combination of anti- fibrosis therapies with TCR-T cell therapy will lead to new avenues of anti-cancer therapy that can become the treatment for nonimmunogenic “cold” tumors.

过继细胞疗法 (ACT)，包括两种方式： 工程 T 细胞受体 (TCR) 疗法 和嵌合抗原受体（CAR）T细胞疗法目前处于癌症免疫疗法的最前沿。 虽然CAR-T疗法在治疗造血系统癌症方面取得了临床成功并获得批准 FDA尚未确认其治疗实体瘤的临床疗效。相比之下，TCR-T细胞 尽管主要障碍是解除和抑制实体瘤，但治疗似乎对实体瘤更有希望。 由含有坚硬且结构复杂的细胞外基质的纤维化肿瘤基质改造的 T 细胞 基质（ECM）、癌症相关成纤维细胞（CAF）和各种免疫细胞，例如肿瘤相关细胞 巨噬细胞（TAM）。随着对 TCR-T 细胞疗法的深入临床研究， CAR-T疗法研究数量多，亟需了解相互作用机制 TCR-T 细胞和肿瘤基质之间。该项目的目标是剖析和理解 TCR-T 细胞与纤维化肿瘤基质之间的机械免疫相互作用，以改善 TCR-T 细胞免疫疗法。主要假设是抗纤维化策略可以减少肿瘤相关的 纤维化并增强TCR-T细胞克服免疫抑制微环境的能力，从而 从而提高治疗效果。该研究团队由一位医学科学家组成，他开创了 双管齐下的 TCR-T 细胞疗法（超级 T 细胞），靶向肿瘤抗原 NY-ESO-1 并阻断 同时免疫抑制 TGF-β 信号传导，目前正在进行由 NIH 和 DoD 资助的临床试验。这 第二个团队成员是一名生物医学工程师，专门研究纤维化的器官模型 疾病和抗纤维化药物的开发。在当前的研究中，新的微生理肿瘤基质生态位 将开发模型来研究 TCR-T 细胞与纤维化基质因子之间的相互作用 联合或不联合抗纤维化治疗。目的包括调查竞争效应 TCR-T 细胞上的纤维化因子，以确定抑制 TCR-T 细胞的主要纤维化因子 功能，模拟肿瘤基质中的动态纤维化进展，并研究不同的作用 纤维化抑制、降解和阻断 TCR-T 细胞的功能并研究 抗纤维化治疗与TCR-T细胞联合治疗的机制和疗效。这个项目很创新 因为这项研究剖析了肿瘤纤维化基质抑制转基因TCR-T的机制 细胞将有助于确定治疗靶点，以设计和优化未来的纤维化靶向 T 细胞 疗法。 NY-ESO-TCR-T和Super T细胞的比较将直接有利于我们正在进行的临床 研究并帮助评估这些治疗性 T 细胞。预计结合抗 TCR-T 细胞疗法的纤维化治疗将带来抗癌治疗的新途径，可能成为 治疗非免疫原性“冷”肿瘤。