I-Corps: Bioengineered Chimeric Antigen Receptor (CAR) Chips for Screening CAR T-Cell Immunotherapy

这个i-Corps项目的更广泛的影响/商业潜力是开发嵌合抗原受体(CAR)T细胞芯片技术，以提高癌症治疗的成功率，缩短CAR T细胞免疫治疗的周期，使整个方法具有成本效益，并最终改善患者的福利。这项技术可能在资源匮乏的社区特别有效，在那里，目前的CAR T细胞治疗负担不起。此外，CAR-T芯片技术可能会带来药物开发的范式转变：降低开发成本，提高新开发的CAR T细胞产品在临床试验中的总体合格率。这个I-Corps项目是基于一种改进的CAR T细胞疗法的开发，该疗法对骨髓中多样化的、进化的免疫抑制环境进行全面分析，并建立一个强大的系统来探索CAR-T细胞与肿瘤免疫微环境之间的相互作用。目前，研究B细胞急性淋巴母细胞性淋巴瘤(B-ALL)的病理生理学和检测CAR T细胞功能的方法主要采用常规的体外细胞培养和动物模型。这些方法未能概括人类免疫系统，从而无法全面应用于临床。新的基于微流控的CAR-T芯片平台通过在芯片上概括患者特定的白血病骨髓微环境，可能为筛选和改进CAR T细胞治疗提供一条新的途径。这项拟议的技术可以对CAR T细胞免疫疗法以及替代疗法的患者特异性反应进行快速、经济有效和高通量的评估。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this I-Corps project is the development of Chimeric Antigen Receptor (CAR) T-cell Chip technology to improve the success rate of cancer treatment and shorten the cycle of CAR T-cell immunotherapy, making the entire approach cost-effective and ultimately improving patient welfare. This technology may be especially impactful in low resource communities where current CAR T-cell treatments are unaffordable. Moreover, the CAR-T Chip technology may provide a paradigm shift in drug development: reducing development costs and improving the overall pass rate of newly developed CAR T-cell products in clinical trials. This I-Corps project is based on the development of an improved CAR T-cell therapy with a holistic analysis of the diverse, evolutionary immunosuppressive milieus in the bone marrow and a robust system to probe the interactions between CAR-T cells and the tumor immune microenvironment. Currently, conventional in vitro cell culture and animal models are used to study B-cell acute lymphoblastic lymphoma (B-ALL) pathophysiology and test CAR T-cell functionality. These methods fail to recapitulate the human immune system and thus their clinical full-flanged usage. The new microfluidics-based CAR-T Chip platform may provide a new avenue for screening and improving CAR T-cell therapy by recapitulating patient-specific leukemic bone marrow microenvironment on a chip. The proposed technology may enable a rapid, cost-effective, and high-throughput evaluation of patient-specific response to CAR T-cell immunotherapy, as well as alternative treatments.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.