Enhancing CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor

通过嵌合受体加强疫苗增强 CAR-T 细胞对抗实体瘤的活性

• 批准号: 10540783
• 负责人: Darrell J Irvine
• 金额: $ 33.2万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540783
• 关键词: Address; Adjuvant; Adoptive Cell Transfers; Adoptive Transfer; Albumins; Animals; Antigen Presentation; Antigen-Presenting Cells; Antigens; Binding; Biodistribution; Biological Models; Blood; Blood Circulation; Cancer Vaccines; Cell Count; Cell Culture Techniques; Cell Therapy; Cell membrane; Cells; Clinical; Clinical Trials; Disease remission; Dose; Engraftment; Ensure; Exhibits; Face; Fluorescein-5-isothiocyanate; Hematologic Neoplasms; Human; Immune system; Immunization; Immunocompetent; Immunotherapy; Injections; Investments; Language; Licensure; Ligands; Lipids; Lymph; Membrane; Memory; Molecular; Molecular Chaperones; Molecular Target; Patients; Peptide Vaccines; Peptides; Phenotype; Phospholipids; Polymers; Population; Property; Public Health; Regimen; Rejuvenation; Research; Role; Safety; Secondary Immunization; Solid Neoplasm; Surface Antigens; System; T cell response; T cell therapy; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Vaccinated; Vaccination; Vaccine Adjuvant; Vaccines; amphiphilicity; booster vaccine; cancer immunotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; design; draining lymph node; genetically modified cells; in vivo; leukemia/lymphoma; lymph nodes; melanoma; mouse model; neoplastic cell; peptide amphiphiles; receptor; response; safety assessment; success; synthetic biology; technology platform; tumor; uptake

Project Summary/Abstract 30 lines or less: Adoptive cell therapy (ACT) with chimeric antigen receptor (CAR) T cells has shown dramatic clinical responses in hematologic cancers, with a high proportion of durable complete remissions elicited in leukemias and lymphomas. This success has led to a strong commercial investment establishing adoptive cell therapy as a viable clinical therapy and the first licensure of CAR-T therapy by the FDA in 2017. However, achieving the full promise of CAR-T ACT, especially in solid tumors, will require further advances in this form of cellular therapy. A key challenge is maintaining a sufficient pool of functional CAR-T cells in vivo. In addition, even in hematologic tumors treated effectively with CAR T cells, chemotherapeutic lymphodepletion regimens with high toxicity are often required to ensure the engraftment and initial expansion of the donor cells. We recently discovered an efficient strategy for molecularly targeting peptide vaccines and vaccine adjuvants to lymph nodes, through the use of albumin-binding phospholipid-polymer linkers conjugated to antigens/molecular adjuvants. Albumin constitutively traffics from blood to lymph, and serves as an effective chaperone to concentrate these “amphiphile-vaccine” (amph-vax) components in lymph nodes that would otherwise be rapidly dispersed in the bloodstream following parenteral injection. However, these lipid-polymer conjugates also exhibit the property that they insert in cell membranes on arrival in lymph nodes. We propose here to exploit these dual lymph node targeting and membrane-decorating properties of amph-vax molecules to create a booster vaccine for CAR T cells, which can be used to repeatedly expand and rejuvenate CAR-T directly in vivo- in native lymph nodes and/or tumors. To evaluate this approach in the presence of a complete host immune system, we will test this concept both with human T cells and with an immunocompetent syngeneic mouse model of melanoma recently developed by our lab. Our specific aims are to (1) Characterize the biology of synthetic antigen presentation of amphiphile-ligands from the surface of antigen presenting cells to CAR T cells in vivo, (2) to demonstrate an amph-vax design generalizable to any CAR, (3) to evaluate the capacity of a CAR-T vaccine to expand T cells with enhanced functionality and persistence in vivo, and (4) to test the utility of intratumoral amph-vax delivery to enhance CAR-T and endogenous T cell priming in tandem. These studies will establish a robust technology platform to transform multiple aspects of adoptive cell therapy and address key limitations in existing ACT therapeutic strategies.

项目摘要/摘要 30 行或更少： 使用嵌合抗原受体 (CAR) T 细胞的过继细胞疗法 (ACT) 已显示出显着效果 血液癌症的临床反应，其中持久完全缓解的比例很高 这一成功带来了强劲的商业前景。 投资建立过继细胞疗法作为可行的临床疗法和第一个许可证 FDA于2017年批准了CAR-T疗法。然而，实现CAR-T ACT的全部承诺， 尤其是在实体瘤中，将需要这种形式的细胞治疗的进一步进展。 此外，即使在体内，仍面临着维持足够的功能性 CAR-T 细胞库的挑战。 CAR T 细胞、化疗性淋巴细胞清除有效治疗血液肿瘤 通常需要具有高毒性的方案来确保植入和初始扩张 我们最近发现了一种有效的分子靶向肽策略。 通过使用白蛋白结合将疫苗和疫苗佐剂接种到淋巴结 与抗原/分子佐剂组成型缀合的磷脂-聚合物接头。 从血液到淋巴液的运输，并作为有效的伴侣来集中这些 淋巴结中的“两亲疫苗”（amph-vax）成分，否则会迅速传播 然而，这些脂质聚合物在肠胃外注射后分散在血液中。 缀合物还表现出到达淋巴液后插入细胞膜的特性 我们在这里建议利用这些双重淋巴结靶向和膜装饰。 利用 amph-vax 分子的特性来创建 CAR T 细胞的加强疫苗，该疫苗可以 用于直接体内重复扩增和恢复 CAR-T - 在天然淋巴结和/或 为了在完整的宿主免疫系统存在的情况下评估这种方法，我们将 用人类 T 细胞和具有免疫功能的同系小鼠测试这个概念 我们实验室最近开发的黑色素瘤模型的具体目标是（1）表征。 抗原表面两亲配体合成抗原呈递的生物学 在体内将细胞呈递给 CAR T 细胞，(2) 展示可推广到的 amph-vax 设计 任何 CAR，(3) 评估 CAR-T 疫苗以增强的方式扩增 T 细胞的能力 体内功能和持久性，以及（4）测试瘤内 Amph-vax 递送的效用 这些研究将建立一个协同增强 CAR-T 和内源性 T 细胞启动的方法。 强大的技术平台可以改变过继细胞疗法的多个方面并解决 现有 ACT 治疗策略的主要局限性。