Biomaterial Scaffolds for In Vivo CAR T Cell Manufacture

用于体内 CAR T 细胞制造的生物材料支架

基本信息

批准号：
10739094
负责人：
Yevgeny Brudno
金额：
$ 17.21万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10739094
关键词：
3-Dimensional Adopted Alginates Allogenic Architecture Autologous B lymphoid malignancy Biocompatible Materials Blood CAR T cell therapy CD28 gene CD3 Antigens CXCL10 gene Cell Count Cell Differentiation process Cell Proliferation Cell physiology Cells Cellular biology Chemicals Circulation Clinical Consumption Data Devices Disease Disease Progression Dose Dose Limiting Drug Delivery Systems Encapsulated Engineering Engraftment Ensure Generations Goals Hematopoietic Neoplasms Immune Implant In Situ In Vitro Interleukin-2 Interleukins Kinetics Liquid substance Longevity Lymphocyte Malignant Neoplasms Measures Mediating Medical Modeling Patients Phenotype Procedures Process Production Public Health Publishing Recurrent tumor Resistance Retroviral Vector Signal Transduction Solid Solid Neoplasm Specialist Stream Stress Tests T-Cell Activation T-Lymphocyte Technology Therapeutic Time Translating Viral Viral Vector Work biomaterial compatibility bioscaffold cellular transduction chemokine chimeric antigen receptor chimeric antigen receptor T cells clinically relevant cost engineered T cells fighting graft vs host disease high reward high risk immunogenicity improved in vivo innovation leukemia/lymphoma manufacture manufacturing facility manufacturing process mechanical properties mouse model particle patient population prevent procedure cost programs recruit response scaffold success tumor

项目摘要

PROJECT SUMMARY CAR-T cell therapy has revolutionized the treatment of liquid tumors, including leukemia and lymphoma, and hold enormous promise for treatment of solid cancers as well. However, despite their unprecedented clinical success, widespread utilization of this therapy is hampered by the lengthy and labor-intensive manufacturing procedures. CAR-T cell manufacturing is both laborious and time-consuming, results in very high costs of therapy (~$500,000). The long manufacturing time creates delays of weeks or months to infuse CAR-T cells to patients with rapidly progressing disease. Extensive ex vivo cell manipulation creates cell products with heterogeneous composition and terminal differentiation that limit CAR-T cell engraftment and persistence. Effort to overcome these limitations have focused on closed and automatic manufacturing devices to contain the labor needed to manufacture CAR-T cells ex vivo, and allogeneic off-the-shelf CAR-T cells have been proposed to overcome the need of CAR-T cell manufacturing for each single patient. These technologies are promising, but reducing the time, costs and regulatory burden of manufacturing or eliminating ex vivo procedures entirely remains a critical unmet need. In vivo generation of autologous CAR-T cells would eliminate the ex vivo procedures, prevent the terminal differentiation of ex vivo expanded CAR-T cells and ensure the potency and longevity of autologous T cells as compared to allogeneic CAR-T cell products that are extensively manipulated to prevent rejection and graft-versus-host disease. This proposal outlines the first steps in a highly innovative high-risk/high-reward effort to develop bioinstructive biomaterials scaffolds that generate CAR-T cells entirely within the patient and produce CAR-T cells with improved efficacy and persistence. Our endeavor is built on significant published and prelimi- nary data demonstrating that our biomaterial scaffolds already efficiently activate and mediate CAR-T cell trans- duction in vitro and efficiently recruit and release CAR-T cells in vivo and reduce CAR-T manufacturing times from weeks to a single day. We propose that biocompatible alginate biomaterial scaffolds can be modified to encapsulate T cell-attracting chemokines to recruit T cells to the scaffold. After recruitment, the biomaterial scaf- folds will provide αCD3/CD28 signaling to activate the T cells. After activation, T cell-specific viral particles either already present in the biomaterial or administered to the biomaterial as a separate step will transduce the T cells, generating tumor-specific CAR-T cells in situ in manner compatible with irradiative lymphodepletion. Finally, interleukin signaling in the scaffold will expand and promote release of formed CAR-T cells for systemic efficacy. This approach could have enormous clinical impact by significantly reducing therapy costs and dramatically expanding the patient population benefiting from CAR-T-cell therapy. We expect that these studies will provide a foundational technology for CAR-T cells manufacturing and promote widespread patient access. In addition to the clear application in cancer, however, this rational, materials-based approach for cellular manufacturing could be adopted to program therapeutic lymphocytes in solid tumors and for other diseases.

项目概要 CAR-T细胞疗法彻底改变了液体肿瘤的治疗，包括白血病和淋巴瘤，然而，尽管它们的临床效果史无前例，但它在治疗实体癌症方面也具有巨大的前景。尽管该疗法取得了成功，但其广泛使用却受到漫长且劳动密集型制造的阻碍 CAR-T细胞制造过程既费力又耗时，导致治疗成本非常高。（约 500,000 美元）。较长的制造时间导致向患者输注 CAR-T 细胞的时间延迟数周或数月。随着疾病快速进展，广泛的离体细胞操作产生了具有异质性的细胞产物。限制 CAR-T 细胞植入和持久性的组成和终末分化需要克服。这些限制主要集中在封闭式自动化制造设备上，以容纳生产所需的劳动力。离体制造 CAR-T 细胞，同种异体现成 CAR-T 细胞已被提出来克服为每个患者制造 CAR-T 细胞的需求这些技术很有前景，但减少了成本。制造或完全消除离体程序的时间、成本和监管负担仍然是一个关键体内产生自体 CAR-T 细胞将消除体外程序，防止体外扩增的 CAR-T 细胞的终末分化，确保自体 T 细胞的效力和寿命细胞与同种异体 CAR-T 细胞产品相比，同种异体 CAR-T 细胞产品经过广泛操作以防止排斥和该提案概述了高度创新的高风险/高回报工作的第一步。开发生物指导性生物材料支架，完全在患者体内生成 CAR-T 细胞并产生我们的努力建立在显着发表的和初步的基础上。大量数据表明我们的生物材料支架已经有效激活和介导 CAR-T 细胞转化体外诱导，体内有效招募和释放 CAR-T 细胞，减少 CAR-T 制造时间我们建议可以将生物相容性藻酸盐生物材料支架修改为封装 T 细胞吸引趋化因子以将 T 细胞招募到支架上。折叠将提供αCD3/CD28信号来激活T细胞，激活后，T细胞特异性病毒颗粒。已经存在于生物材料中或作为单独步骤施用至生物材料将转导T细胞，以与辐射淋巴细胞清除兼容的方式原位生成肿瘤特异性 CAR-T 细胞。支架中的白细胞介素信号传导将扩展并促进形成的 CAR-T 细胞的释放，以实现全身功效。这种方法可以通过降低治疗成本和显着地产生巨大的临床影响我们预计这些研究将扩大受益于 CAR-T 细胞疗法的患者群体。 CAR-T 细胞制造的基础技术，并促进广泛的患者使用。然而，这种合理的、基于材料的细胞制造方法在癌症中的明确应用可以可用于对实体瘤和其他疾病中的治疗性淋巴细胞进行编程。