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

• 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
• 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

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.

项目摘要 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， 对实体癌的治疗也有巨大的希望。然而，尽管他们前所未有的临床 尽管这种疗法取得了成功，但由于冗长和劳动密集型的制造过程， 程序. CAR-T细胞制造既费力又耗时，导致治疗成本非常高 （约50万美元）。漫长的制造时间造成了数周或数月的延迟，无法将CAR-T细胞输注给患者 病情迅速恶化广泛的离体细胞操作产生具有异质性的细胞产物。 这可能是由于CAR-T细胞的组成和终末分化限制了CAR-T细胞的植入和持久性。努力克服 这些限制集中在封闭和自动化的制造设备上 体外制造CAR-T细胞，并且已经提出了同种异体现成CAR-T细胞来克服CAR-T细胞的缺陷。 需要为每个患者制造CAR-T细胞。这些技术是有前途的，但减少 制造或完全消除离体程序的时间、成本和监管负担仍然是关键的 未满足的需求自体CAR-T细胞的体内产生将消除离体程序，防止肿瘤细胞的增殖。 体外扩增的CAR-T细胞的终末分化，并确保自体T细胞的效力和寿命。 与广泛操作以防止排斥的同种异体CAR-T细胞产物相比， 移植物抗宿主病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，完全在患者体内产生CAR-T细胞， CAR-T细胞具有改善的功效和持久性。我们的奋进是建立在重要的出版和prelimi- 几乎没有数据表明我们的生物材料支架已经有效地激活和介导CAR-T细胞跨膜转运。 在体外诱导并在体内有效募集和释放CAR-T细胞，并减少CAR-T制造时间 从几周到一天我们建议，生物相容性藻酸盐生物材料支架可以修改， 包封吸引T细胞的趋化因子以将T细胞募集到支架上。招募后，生物材料scaf- 折叠将提供α CD 3/CD 28信号以激活T细胞。活化后，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的步骤给予生物材料将使T细胞增殖， 以与辐射淋巴细胞耗竭相容的方式原位产生肿瘤特异性CAR-T细胞。最后， 支架中的白细胞介素信号传导将扩增并促进所形成的CAR-T细胞的释放以用于全身功效。 这种方法可以通过显着降低治疗成本和显着降低成本来产生巨大的临床影响。 扩大受益于CAR-T细胞疗法的患者群体。我们希望这些研究能够提供 这是CAR-T细胞制造的基础技术，并促进广泛的患者获取。除了 然而，这种合理的、基于材料的细胞制造方法， 可用于编程实体瘤和其他疾病的治疗性淋巴细胞。