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: 10322393
• 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/10322393
• 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; Research; Role; Safety; Secondary Immunization; Solid Neoplasm; Surface Antigens; System; T cell response; T cell therapy; T-Lymphocyte; Technology; Testing; Therapeutic; Toxic effect; Vaccinated; Vaccination; Vaccine Adjuvant; Vaccine Design; Vaccines; base; booster vaccine; cancer immunotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; draining lymph node; genetically modified cells; in vivo; leukemia/lymphoma; lymph nodes; melanoma; mouse model; neoplastic cell; peptide amphiphiles; receptor; response; success; synthetic biology; tumor; vaccine acceptance; vaccine delivery

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： 用嵌合抗原受体（CAR）T细胞的收养细胞疗法（ACT）显示出戏剧性的 血液学癌症中的临床反应，耐用的耐用性很高 在白血病和淋巴瘤中引起的还原。这种成功导致了一个强大的广告 投资建立自适应细胞疗法作为可行的临床疗法和首次许可 FDA在2017年进行的CAR-T治疗。但是，实现了Car-T法案的全部承诺， 特别是在实体瘤中，将需要在这种形式的细胞疗法中进一步进步。钥匙 挑战是在体内维持足够的功能性CAR-T细胞。另外，即使在 用CAR T细胞有效治疗的化学治疗性淋巴结肿瘤有效治疗的血液学肿瘤 通常需要高毒性的方案以确保植入和初始膨胀 供体细胞。我们最近发现了一种有效靶向肽的有效策略 通过使用白蛋白结合，疫苗和疫苗调节器淋巴结 磷脂 - 聚合物接头与抗原/分子调节剂结合。组成性白蛋白 从血液到淋巴的交通，并用作有效的伴侣来集中这些 淋巴结中的“ Amphiphile-vaccine”（Amph-vax）成分，否则会很快 肠胃外注射后分散在血液中。但是，这些脂质聚合物 结合物还表现出它们在到达淋巴时插入细胞膜中插入的特性 节点。我们在这里建议探索这些双淋巴结靶向和膜装饰 Amph-vax分子的特性为CAR T细胞创建增强疫苗，可以是 用于在天然淋巴结和/或的体内反复扩展和恢复直接在体内的CAR-T 肿瘤。为了在完整的宿主免疫系统的存在下评估这种方法，我们将 用人类T细胞和免疫能力的同性小鼠测试这个概念 黑色素瘤模型最近由我们的实验室开发。我们的具体目的是（1）表征 来自抗原表面的两亲体呈合成抗原的生物学 （2）向汽车T细胞呈现细胞，以证明可推广到的Amph-Vax设计 任何汽车，（3）评估CAR-T疫苗通过增强的T细胞扩展T细胞的能力 体内功能和持久性，（4）测试肿瘤内Amph-Vax递送的效用 增强串联中的CAR-T和内源性T细胞启动。这些研究将建立一个 强大的技术平台转变自适应细胞疗法的多个方面并解决 现有ACT治疗策略的关键局限性。