Adoptive T Cell Therapy for Pancreatic Cancer

胰腺癌过继性 T 细胞疗法

• 批准号: 10222622
• 负责人: Cassian Yee
• 金额: $ 62.38万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222622
• 关键词: Address; Adoptive Cell Transfers; Adoptive Transfer; Antigen Targeting; Antigens; Blood Cells; CD28 gene; CD8-Positive T-Lymphocytes; COL6A3; Cancer Etiology; Cell Separation; Cell Surface Proteins; Cell Therapy; Cessation of life; Clinical; Clinical Research; Clinical Trials; Cutaneous Melanoma; Disease; Dose; Epitope spreading; Epitopes; Frequencies; Future; Genetic; Immune; Immune checkpoint inhibitor; Immunotherapy; In Vitro; Infusion procedures; Intercept; Interferon Type II; Lead; Ligands; Malignant neoplasm of pancreas; Memory; Modification; Mutation; PD-1 blockade; PD-1/PD-L1; PDL1 pathway; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phase; Phase Ib Trial; Population; Process; Refractory; Resuscitation; Safety; Signal Transduction; Source; Specificity; Surface; Survival Rate; T cell therapy; T memory cell; T-Cell Activation; T-Lymphocyte; Therapeutic; Time; Tumor-Infiltrating Lymphocytes; advanced pancreatic cancer; antigen-specific T cells; base; cell type; checkpoint inhibition; chimeric antigen receptor; clinical efficacy; cohort; conventional therapy; first-in-human; immune checkpoint blockade; immunogenic; immunogenicity; improved; in vivo; mortality; neoplastic cell; novel; pancreatic cancer patients; peripheral blood; phase II trial; programmed cell death protein 1; rare cancer; response; safety and feasibility; standard care; targeted treatment; tumor; tumor microenvironment

Pancreatic cancer will be responsible for over 44,000 deaths in the US this year and is currently the 3rd leading cause of cancer mortality; survival in this disease has not changed in the last 40 years. Although immune checkpoint inhibitors have emerged as highly effective approaches for tumors with high mutational burden, such is not the case with pancreatic cancer which lacks a significant endogenous tumor-reactive T cell population. Adoptively transfer of antigen-specific T cells would provide an effector substrate for immune checkpoint inhibition and we reason that such a combination strategy would be desirable. In this proposal we address two major challenges to advancing the use of adoptive cellular therapy (ACT) for pancreatic cancers: 1. a paucity of proven immunogenic targets for pancreatic cancer and, 2., a means of rapidly deploying antigen-specific cellular therapy targeting such antigens. In this proposal we plan to target a tumor cell-associated target antigen (VCY) and a tumor stroma-associated target (COL6A3), both highly prevalent (> 70% of tumors), and highly immunogenic. Our scientific premise is that strategies that address the lack of tumor-reactive T cells in pancreatic cancer, where the mutational burden and immunogenicity is significantly lower, would be desirable and achievable by the adoptive transfer of tumor-reactive T cells recognizing pancreatic cancer-associated antigens. Adoptive cellular therapy (ACT) is a promising form of immunotherapy that involves the ex vivo isolation and expansion of antigen-specific T cells for infusion. Based on the premise that strategies to extend in vivo persistence of transferred T cells and induce antigen-spreading will lead to improved clinical response following ACT, we hypothesize that adoptive transfer of long-lasting central memory type T cells in combination with PD1 blockade will lead to extended in vivo survival and enhanced activation of endogenous T cells recognizing non-targeted antigens (antigen-spreading). Our ETC (endogenous T cell therapy) approach to ACT was to pioneer a strategy that uses peripheral blood as a source of T cells. Using a combination of IL-21 priming (to enrich for central memory type T cells) and tetramer-guided cell sorting, we can routinely isolate rare tumor-reactive T cells from the peripheral blood ( < 1:100,000) and expand these to a > 20 billion uniformly defined central memory – type specific T cells with defined specificity and high replicative capacity as demonstrated by several prior studies demonstrating months-long in vivo persistence at frequencies 1-10 % commensurate with durable clinical responses. We propose a Phase IB trial targeting COL6A3 and VCY in patients with refractory pancreatic adenocarcinoma, first in a dose escalation cohort, and when a dose has been identified, an expansion cohort in combination with PD1 blockade.

胰腺癌今年将导致美国超过 44,000 人死亡，目前是第三大癌症 癌症死亡的主要原因；过去 40 年来，这种疾病的生存率没有改变。虽然 免疫检查点抑制剂已成为治疗高发肿瘤的高效方法 突变负担，但胰腺癌的情况并非如此，因为胰腺癌缺乏显着的内源性 肿瘤反应性 T 细胞群。抗原特异性 T 细胞的过继转移将提供效应子 免疫检查点抑制的底物，我们认为这种组合策略是 理想的。在本提案中，我们解决了推进收养细胞使用的两个主要挑战 胰腺癌治疗（ACT）：1. 缺乏已证实的胰腺癌免疫原性靶点 2.快速部署针对此类抗原的抗原特异性细胞疗法的方法。在这个 我们计划针对肿瘤细胞相关靶抗原（VCY）和肿瘤基质相关抗原 靶点 (COL6A3)，既高度流行（> 70% 的肿瘤），又具有高度免疫原性。我们的科学 前提是解决胰腺癌中缺乏肿瘤反应性 T 细胞的策略，其中 突变负担和免疫原性显着降低，这将是可取的并且可以通过 识别胰腺癌相关抗原的肿瘤反应性 T 细胞的过继转移。 过继细胞疗法（ACT）是一种有前景的免疫疗法，涉及离体分离 以及扩增抗原特异性 T 细胞用于输注。基于策略延伸的前提 转移的 T 细胞在体内持续存在并诱导抗原扩散将导致改善 ACT 后的临床反应，我们假设持久中枢记忆的过继转移 T 型细胞与 PD1 阻断相结合将导致体内存活时间延长并增强 激活识别非目标抗原的内源性 T 细胞（抗原扩散）。 我们针对 ACT 的 ETC（内源性 T 细胞疗法）方法是开创一种使用外周血的策略 血液作为T细胞的来源。结合使用 IL-21 启动（以丰富 T 型中枢记忆） 细胞）和四聚体引导的细胞分选，我们可以常规地从细胞中分离出罕见的肿瘤反应性 T 细胞 外周血 (< 1:100,000) 并将其扩展到 > 200 亿个统一定义的中央存储器 – 多种类型的特异性 T 细胞具有明确的特异性和高复制能力 先前的研究表明，在频率为 1-10% 的情况下，可在体内持续数月之久 持久的临床反应。我们建议针对 COL6A3 和 VCY 患者开展一项 IB 期试验 难治性胰腺癌，首先在剂量递增队列中，并且当剂量已经 确定了一个与 PD1 阻断相结合的扩展队列。