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

项目概要/摘要30行或以下： 使用嵌合抗原受体（CAR）T细胞的免疫细胞疗法（ACT）已经显示出显著的 血液系统癌症的临床缓解，持久完全缓解的比例较高， 白血病和淋巴瘤引起的缓解。这一成功导致了一个强大的商业 投资建立过继性细胞治疗作为一种可行的临床治疗和第一个许可证 2017年，FDA批准了CAR-T疗法。然而，实现CAR-T法案的全部承诺， 特别是在实体瘤中，将需要这种形式的细胞疗法的进一步发展。一个关键 挑战是在体内维持足够的功能性CAR-T细胞库。此外，即使在 用CAR T细胞有效治疗血液肿瘤，化疗淋巴细胞耗竭 通常需要具有高毒性的方案来确保植入和初始扩增， 捐献者的细胞我们最近发现了一种有效的分子靶向肽的策略， 疫苗和疫苗佐剂的淋巴结，通过使用白蛋白结合 与抗原/分子佐剂缀合的磷脂-聚合物接头。白蛋白组成型 运输从血液到淋巴，并作为一个有效的伴侣集中这些 淋巴结中的“两亲性疫苗”（amph-vax）成分，否则这些成分会迅速被 在肠胃外注射后分散在血流中。然而，这些脂质聚合物 偶联物还表现出它们在到达淋巴时插入细胞膜的性质 结我们在这里建议利用这些双重淋巴结靶向和膜装饰 amph-vax分子的特性，以创建CAR T细胞的加强疫苗， 用于直接在体内-在天然淋巴结和/或淋巴结中重复扩增和再生CAR-T， 肿瘤的为了在完整的宿主免疫系统存在下评估这种方法，我们将 用人类T细胞和具有免疫活性的同基因小鼠来测试这一概念 我们实验室最近开发的黑色素瘤模型。我们的具体目标是：（1） 抗原表面两亲配体的合成抗原呈递生物学 （2）证明可推广到CAR T细胞的amph-vax设计， （3）评估CAR-T疫苗扩增T细胞的能力， 功能性和体内持久性，以及（4）测试瘤内amph-vax递送的效用 以增强CAR-T和内源性T细胞的串联引发。这些研究将建立一个 强大的技术平台，可改变过继细胞治疗的多个方面， 现有ACT治疗策略的主要局限性。

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.