Enhancing engineered T cell therapeutic efficacy for the treatment of pancreatic ductal adenocarcinoma

项目总结 胰腺导管腺癌(PDA)是一种高度致命性的恶性肿瘤，5年总存活率为10%。 致命性是由于诊断晚、转移早和治疗耐药所致。掌上电脑的一个显著特点 是强健的纤维炎症和抑制肿瘤的微环境，它压缩血管和 限制药物的使用。这种肿瘤微环境也被认为干扰了免疫疗法，而免疫疗法是 改变了许多其他癌症适应症的护理标准。肿瘤抗原特异性T细胞是 负责调节免疫疗法的治疗效果。虽然人们已经了解了很多关于 胰腺肿瘤微环境中的抑制性细胞，影响分化程序的因素 在这种疾病中，对抗原特异性T细胞及其抗肿瘤活性的研究明显不足。我们创建了一个 新型工程化T细胞疗法显示出显著的抗肿瘤和抗间质活性 难以治疗基因工程PDA动物模型，该模型概括了人类疾病的许多方面， 包括对免疫治疗的反应。T细胞被设计为表达一种肿瘤反应性T细胞受体 间硫蛋白在肿瘤细胞中高表达，而在正常细胞中低表达，是安全的，可以破坏 基质，改变髓系细胞的组成，诱导客观反应，并显著延长动物的存活。 值得注意的是，工程T细胞优先聚集在原发肿瘤和转移瘤中，挑战了这一教条 那台掌上电脑享有豁免权。基于这一疗效，候选的针对间充质蛋白的T细胞受体将用于 In患者已经被确定，导致了一期临床试验。然而，尽管设计了T细胞持久性 和体内显著的抗肿瘤活性，治愈的一个主要障碍是工程化T细胞的进行性丧失 在抑制性胰腺肿瘤微环境中发挥作用。虽然T细胞的功能和分化 在其他癌症适应症上都得到了很好的研究，但对胰腺肿瘤如何 微环境影响肿瘤抗原特异性T细胞。在这里，我们整合了我们拥有的创新工具 旨在从机制上确定工程T细胞如何介导间质重塑，肿瘤如何适应 并逃避抗肿瘤T细胞，然后利用这一知识开发出尖端的工程化T细胞疗法 与大多数细胞工程方法相比，用于患者治疗具有战略上的进步。我们的 具体目标是：(1)确定工程T细胞如何介导间质重塑；(2)确定其贡献 TCR亲和力和肿瘤微环境对T细胞分化和功能的影响，以及(3)安全性测试 以及针对实体肿瘤的一种新的细胞工程方法的有效性。我们的研究将确定 产生持久抗肿瘤反应的T细胞和肿瘤微环境的特征 免疫治疗为胰腺癌患者的治疗创造了安全持久的临床机会。

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy with a 5-year overall survival of <10%. Lethality is due to late diagnosis, early metastasis and therapeutic resistance. A hallmark characteristic of PDA is the robust fibroinflammatory and suppressive tumor microenvironment that compresses blood vessels and restricts drug access. This tumor microenvironment is also believed to interfere with immunotherapies, which are transforming the standard of care for many other cancer indications. Tumor-antigen specific T cells are responsible for mediating the therapeutic effects of immunotherapy. While much has been learned about suppressive cells within the pancreatic tumor microenvironment, factors that impact the differentiation program of antigen-specific T cells and their antitumor activity is markedly understudied in this disease. We created a novel engineered T cell therapy that shows marked anti-tumor and anti-stromal activity in an aggressive and difficult to treat genetically engineered PDA animal model that recapitulates many aspects of the human disease, including response to immunotherapy. T cells engineered to express a tumor-reactive T cell receptor specific to mesothelin, which is highly expressed by tumor cells yet poorly expressed by normal cells, is safe, destroys the stroma, alters myeloid cell composition, induces objective responses, and significantly prolongs animal survival. Notably, engineered T cells preferentially accumulate in primary tumors and metastasis, challenging the dogma that PDA is immune privileged. Based on this efficacy, candidate T cell receptors specific to mesothelin for use in patients have been identified leading to a Phase 1 clinical trial. However, despite engineered T cell persistence and significant antitumor activity in vivo, a principle obstacle to cure is the progressive loss of engineered T cell function within the suppressive pancreatic tumor microenvironment. While T cell functionality and differentiation are well-studied in other cancer indications, little is understood regarding how the pancreatic tumor microenvironment impacts tumor antigen-specific T cells. Here, we incorporate innovative tools we have developed to identify mechanistically how engineered T cells mediate stromal remodeling, how the tumor adapts and evades anti-tumor T cells, and then use this knowledge to develop a cutting edge engineered T cell therapy for patient treatment with strategic advancements as compared to most cell engineering approaches. Our Specific Aims are to: (1) Identify how engineered T cells mediate stromal remodeling, (2) Identify the contribution of TCR affinity and the tumor microenvironment on T cell differentiation and functionality, and (3) Test the safety and efficacy of a novel cell engineering approach for targeting solid tumors. Our studies will identify characteristics of T cells and the tumor microenvironment that produce durable antitumor responses during immunotherapy to create safe and durable clinical opportunities for pancreatic cancer patient treatment.