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

增强工程化 T 细胞治疗胰腺导管腺癌的疗效

基本信息

批准号：
10674877
负责人：
Ingunn Margarete Stromnes
金额：
$ 34.75万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-16 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10674877
关键词：
Adoptive Cell Transfers Advanced Malignant Neoplasm Affinity Animal Model Animals Antigen Presentation Antigens Antitumor Response Biological Assay Blood Vessels Bypass CRISPR/Cas technology Cancer Etiology Cancer Model Cancer Patient Carcinoma Cell Death Cell Therapy Cell physiology Cells Characteristics Chronic Clinical Coculture Techniques Cytometry Cytotoxic T-Lymphocytes Data Defect Diagnosis Disease Endothelial Cells Extracellular Matrix Fibroblasts Genes Genetic Engineering Human Immune Immune Evasion Immunotherapy In Vitro Knock-in Mouse Knowledge Learning Legal patent Macrophage Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mediating Mesenchymal Modeling Mus Myelogenous Myeloid Cells Neoplasm Metastasis Normal Cell Pancreatic Ductal Adenocarcinoma Patients Pharmaceutical Preparations Phase I Clinical Trials Preclinical Testing Predisposition Primary Neoplasm Production Proteins Receptor Signaling Regulatory T-Lymphocyte Reporter Resistance Role Safety Signal Transduction Solid Neoplasm Specificity T cell differentiation T cell infiltration T cell response T cell therapy T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Therapeutic Effect Toxic effect Toxicity Tests Translating Treatment Efficacy Tumor Antigens Tumor Immunity Xenograft Model antigen-specific T cells antitumor effect base editor cell type cellular engineering chimeric antigen receptor comparative efficacy cytokine effective therapy engineered T cells exhaustion human disease immune checkpoint blockade immunoregulation in vivo innovation mesothelin mortality mouse model mutant neoplastic cell novel overexpression pancreatic cancer patients pancreatic neoplasm pre-clinical progenitor programmed cell death protein 1 programs public health relevance response safety testing screening standard of care stem targeted treatment therapy design therapy resistant tool transcription factor tumor tumor microenvironment tumor xenograft vector

项目摘要

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.

项目概要胰腺导管腺癌（PDA）是一种高度致命的恶性肿瘤，5年总生存率<10%。致死率是由于晚期诊断、早期转移和治疗耐药造成的。 PDA 的标志性特征是强大的纤维炎症和抑制性肿瘤微环境，可压缩血管并限制药物获取。这种肿瘤微环境也被认为会干扰免疫疗法，改变许多其他癌症适应症的护理标准。肿瘤抗原特异性 T 细胞是负责介导免疫疗法的治疗效果。虽然已经了解了很多胰腺肿瘤微环境中的抑制细胞，影响分化程序的因素抗原特异性 T 细胞的作用及其抗肿瘤活性在这种疾病中的研究明显不足。我们创建了一个新型工程化 T 细胞疗法，在侵袭性和抗基质活性方面显示出显着的抗肿瘤和抗基质活性难以治疗的基因工程PDA动物模型，概括了人类疾病的许多方面，包括对免疫治疗的反应。 T 细胞被改造来表达特定于肿瘤的肿瘤反应性 T 细胞受体间皮素在肿瘤细胞中高度表达，但在正常细胞中表达较差，是安全的，可以破坏基质，改变骨髓细胞组成，诱导客观反应，并显着延长动物存活时间。值得注意的是，工程化 T 细胞优先在原发肿瘤和转移瘤中积累，挑战了这一教条 PDA 具有免疫特权。基于这种功效，可以使用间皮素特异性的候选 T 细胞受体已在患者中得到鉴定，进入一期临床试验。然而，尽管工程化 T 细胞具有持久性和显着的体内抗肿瘤活性，治愈的主要障碍是工程化 T 细胞的逐渐丧失在抑制性胰腺肿瘤微环境中发挥作用。 T 细胞功能和分化在其他癌症适应症中已得到充分研究，但对于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识别工程 T 细胞如何介导基质重塑、肿瘤如何适应并逃避抗肿瘤 T 细胞，然后利用这些知识开发尖端的工程 T 细胞疗法与大多数细胞工程方法相比，对于患者治疗具有战略性进步。我们的具体目标是：(1) 确定工程化 T 细胞如何介导基质重塑，(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）测试安全性以及针对实体瘤的新型细胞工程方法的功效。我们的研究将确定 T 细胞的特征和肿瘤微环境在过程中产生持久的抗肿瘤反应免疫疗法为胰腺癌患者的治疗创造安全、持久的临床机会。