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细胞疗法已彻底改变了包括白血病和淋巴瘤在内的液体肿瘤的治疗 对固体癌症的治疗也有巨大的希望。然而，尽管他们的临床前所未有 成功，漫长而劳动密集型的制造业阻碍了这种疗法的宽度利用 程序。 CAR-T细胞制造既是实验室又是耗时的，导致治疗成本很高 （〜$ 500,000）。漫长的制造时间会造成数周或数月的延迟，以将CAR-T细胞注入患者 患有快速发展的疾病。广泛的离体细胞操作可创建具有异质性的细胞产品 组成和末端分化，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制造设备上，以控制 已经提出了生产CAR-T细胞，并且已经提出了同种异体式CAR-T细胞来克服 每个患者需要CAR-T细胞制造。这些技术是有希望的，但减少了 制造或消除离体程序的时间，成本和监管燃烧完全是关键 未满足的需求。体内生成自体CAR-T细胞将消除离体程序，防止 离体扩展的CAR-T细胞的末端分化，并确保自体T的效力和寿命 与被广泛操纵以防止排斥和 移植物与宿主病。该提议概述了高度创新的高风险/高回报的第一步 开发生物学结构生物材料支架，这些脚手架完全在患者内部产生CAR-T细胞并产生 CAR-T细胞具有提高效率和持久性。我们的努力建立在大量发表和预定的基础上 NARY数据表明，我们的生物材料支架已经有效地激活并介导了Car-T细胞的转移 体外有效地招募和释放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细胞吸收趋化因子，将T细胞募集到支架上。招募后，生物材料SCAF- 折叠将提供αCD3/CD28信号传导以激活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以生物材料为单独的步骤中的生物材料中，将转导T细胞， 与辐照性淋巴结蛋白相兼容的方式产生肿瘤特异性的CAR-T细胞。最后， 支架中的白介素信号传导将扩展和促进形成的CAR-T细胞的全身效率。 这种方法可能会通过显着降低治疗成本并大大降低治疗成本，从而产生巨大的临床影响 扩大来自CAR-T细胞疗法的患者人群。我们希望这些研究将提供 CAR-T细胞生产并促进宽度的患者进入的基础技术。此外 然而，在癌症中的明确应用，这种基于材料的细胞制造方法可以 在实体瘤和其他疾病中采用用于程序治疗性淋巴细胞。