CAR T platform to treat solid tumors

总结 癌症是全球主要的死亡原因之一。多年来，有几种治疗方法 开发了然而，它们的有效性受到癌细胞异质性的严重限制。因此，在本发明中， 一直需要开发具有改善的结果的治疗方法，例如 免疫疗法利用并增强患者免疫系统的正常能力。值得注意的是，肾脏 细胞癌和卵巢癌被认为是免疫原性的，或“热”癌症，因为肿瘤被浸润， T细胞。这使人们乐观地认为，免疫系统可以被利用，成为一个强大而持久的免疫系统。 对付这些癌症的武器。 嵌合抗原受体（CAR）T细胞疗法已经显示出针对血液肿瘤的显著功效。然而， 由于肿瘤微环境（TME）存在的关键障碍，CAR T细胞无法对抗实体瘤。我们 在本申请中，我提出证明一种新平台的概念验证，该平台可以克服当前的 实体瘤中CAR T细胞治疗的障碍。我们的策略将抗TIM 1 CAR的特异性与 通过两种细胞因子的组合调节TME，导致从免疫抑制转变为免疫抑制。 细胞毒性环境我们的方法利用了招募和激活广泛的 内源性先天性和适应性免疫细胞，包括肿瘤特异性T细胞。Super 2和IL-33 CAR T细胞 在多种鼠实体瘤模型中促进抗肿瘤免疫，并且不受抗原损失的影响， 其作为治疗实体瘤的通用CAR T细胞平台的潜力。目标将包括： 1.设计并评估体外表达抗TIM 1 CAR、Super 2和IL-33的人构建体。目标2. 证明抗TIM 1 CAR T细胞在肿瘤中的双重细胞因子递送的功效的概念验证（POC）。 肾细胞癌（RCC）的人源化模型。

SUMMARY Cancer is one of the leading causes of death worldwide. Over the years, several treatment approaches have been developed. However, their effectiveness is severely limited by the heterogeneity of cancer cells. Thus, there is a constant need for development of therapeutic approaches with improved outcome, such as immunotherapy that utilizes and enhances the normal capacity of the patient's immune system. Of note, renal cell carcinoma and ovarian cancer are considered immunogenic, or “hot” cancers, in that tumors are infiltrated with T cells. This provides optimism that the immune system can be harnessed to be a potent and durable weapon against these cancers. Chimeric antigen receptor (CAR) T cell therapy has shown remarkable efficacy against hematologic tumors. Yet, CAR T cells fail against solid tumors due to key obstacles presented by the tumor microenvironment (TME). We propose in this application to demonstrate proof-of-concept of a novel platform that can overcome the current barrier to CAR T cell therapy in solid tumors. Our strategy combines the specificity of anti-TIM1 CAR with modulation of the TME by a combination of two cytokines, leading to a shift from immunosuppressive to a cytotoxic environment. Our approach capitalizes on the recruitment and activation of a broad repertoire of endogenous innate and adaptive immune cells, including tumor-specific T cells. Super2 and IL-33 CAR T cells promote antitumor immunity in multiple murine solid tumor models and is impervious to antigen loss, highlighting its potential as a universal CAR T cell platform for treatment of solid tumors. Aims will include the following: Aim 1. Design and evaluate human constructs expressing anti-TIM1 CAR, Super2 and IL-33 in vitro. Aim 2. Demonstrate proof of concept (POC) of efficacy of a dual cytokine delivery by anti-TIM1 CAR T cells in a humanized model of Renal cell carcinoma (RCC).