A novel T cell subset with increased potency and persistence for the treatment of solid tumors

项目摘要 癌症是美国第二大死亡原因，尽管人们努力开发小规模的癌症疫苗， 尽管采用分子和生物疗法，但几种实体瘤的5年生存率仍为10%或10%。 少CAR-T疗法最近已被批准用于B细胞恶性肿瘤， 为细胞疗法提供了一个起点，使其成为标准治疗的立足点。然而，在这方面， 将这种成功转化为实体瘤的过程非常缓慢，几乎不存在。主要 其根本原因似乎是缺乏治疗细胞的持久性， 会屈服于肿瘤产生的毒性环境战神免疫疗法分离出了一种独特的 T细胞亚群可以通过抗凋亡机制和在有限的时间内克服这个问题。 自我更新的能力。这些因素，再加上归巢和迁徙能力的提高， 分泌Th 1和Th 17细胞因子的能力，以及通过颗粒酶B和 CD 107 A创造了一种细胞，它有可能根除甚至是大的根深蒂固的肿瘤肿块。在 临床前研究表明，当作为间皮素特异性CAR-T产生时，战神细胞具有 能够消融间皮瘤小鼠模型中的肿瘤， 胰腺模型中的负荷。 我们提出的研究计划将A）提高制造稳健性; B）确定 基于临床疗效和稳健、可扩展的工艺的组合使用的最佳细胞; 以及C）减少制造的时间和成本。我们将通过一系列的 体外测定并通过动物研究进行验证。在这些研究之后，我们将进行最后的 优化，并在IND首次人体研究的路线上进行毒性研究。

Project Summary Cancer is the second leading cause of death in the US and despite efforts to develop small molecule and biological therapies, several solid tumors still have 5-year survival rates of 10% or less. CAR-T therapies have recently been approved for use in B-cell malignancies and have provided a starting point for cell therapies to gain a foothold as standard of care. However, translation of that success into solid tumors has been slow, almost non-existent. The major underlying cause for this appears to be lack of persistence of the therapeutic cell whereby it succumbs to the toxic milieu produced by the tumor. Ares Immunotherapy has isolated a unique T cell subset that can overcome this issue by means of anti-apoptotic mechanisms and at a limited ability to self-renew. These, in combination with an elevated homing and migration capacity, the ability to secrete both Th1 and Th17 cytokines, and direct cytotoxicity via Granzyme B and CD107A create a cell that has the potential to eradicate even large entrenched tumor masses. In preclinical studies the Ares cells, when generated as a mesothelin specific CAR-T, have been able to ablate tumors in a mesothelioma mouse model and greatly reduce tumor burden in a pancreatic model. Our proposed research plan will A) improve manufacturing robustness; B) determine the optimal cell to be used based on a combination of clinical efficacy and a robust, scalable process; and C) reduce the time and cost of manufacture. We will characterize this through a host of in vitro assays and verify with an animal study. Following these studies, we will proceed to final optimizations and conduct a toxicity study in route to an IND for a first-in-man study.