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

项目摘要/摘要不超过30行： 嵌合抗原受体(CAR)T细胞的过继细胞治疗(ACT)显示出戏剧性的效果 血液系统癌症的临床反应，耐久完全的比例很高 白血病和淋巴瘤可引起缓解。这一成功带来了一个强劲的商业 投资建立过继细胞疗法作为一种可行的临床疗法和第一个许可证 FDA于2017年推出CAR-T疗法。然而，要实现CAR-T法案的全部承诺， 尤其是在实体肿瘤中，需要在这种形式的细胞治疗方面取得进一步的进展。一把钥匙 挑战是在体内维持足够的功能CAR-T细胞池。此外，即使在 CAR T细胞联合化疗淋巴清除法有效治疗血液病 通常需要高毒性的方案来确保移植和最初的扩张 捐献细胞。我们最近发现了一种有效的分子靶向多肽的策略 疫苗和疫苗佐剂通过使用白蛋白结合到淋巴结 磷脂--连接到抗原/分子佐剂的聚合物连接物。白蛋白成分 从血液到淋巴的运输，并作为一个有效的伴侣来浓缩这些 “两亲性疫苗”(amph-vax)在淋巴结中的成分，否则会迅速 在肠外注射后分散在血液中。然而，这些脂类聚合物 结合物还表现出它们在到达淋巴时插入细胞膜的性质 节点。我们建议在这里利用这种双重的淋巴结靶向和膜修饰。 Amph-Vax分子的特性可以为CAR T细胞创造增强疫苗，这种疫苗可以 用于在体内直接在天然淋巴结和/或体内重复扩增和恢复CAR-T 肿瘤。为了在存在完整的宿主免疫系统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基因小鼠来测试这一概念 本实验室新近研制的黑色素瘤模型。我们的具体目标是(1)描述 两亲性配体从抗原表面合成抗原递呈的生物学 将细胞呈现给体内的CAR T细胞，(2)展示一种可推广到 任何CAR，(3)评估CAR-T疫苗扩增T细胞的能力 体内的功能性和持久性，以及(4)测试瘤内安非他明给药的效用 同时加强CAR-T和内源性T细胞的启动。这些研究将建立一个 强大的技术平台，可转变采用细胞治疗的多个方面并解决 现有ACT治疗策略的关键限制。

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.