Adoptive T Cell Therapy for Pancreatic Cancer

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。 癌症死亡率的主要原因;在过去的40年里，这种疾病的生存率没有改变。虽然 免疫检查点抑制剂已经成为治疗高表达肿瘤的高效方法。 突变负担，这不是胰腺癌的情况，胰腺癌缺乏显著的内源性 肿瘤反应性T细胞群。抗原特异性T细胞的连续转移将提供效应子 免疫检查点抑制的底物，我们推断这种组合策略将是 令人向往在这项提案中，我们解决了两个主要挑战，以推进使用过继细胞 胰腺癌的ACT疗法：1.胰腺癌的免疫原性靶点缺乏 和，2.一种快速部署靶向这些抗原的抗原特异性细胞治疗的方法。在这 我们计划靶向肿瘤细胞相关的靶抗原（VCY）和肿瘤基质相关的靶抗原。 靶向（C 0 L 6A 3），两者都是高度流行的（> 70%的肿瘤）和高度免疫原性的。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， 突变负荷和免疫原性显著较低，将是期望的并且可通过以下方法实现： 识别胰腺癌相关抗原的肿瘤反应性T细胞的过继转移。 免疫细胞疗法（ACT）是一种很有前途的免疫疗法，其涉及离体分离， 和扩增用于输注的抗原特异性T细胞。基于这样一个前提， 转移T细胞的体内持久性和诱导的抗原扩散将导致改善的 ACT后的临床反应，我们假设长期持久的中央记忆的过继转移 型T细胞与PD 1阻断剂的组合将导致延长的体内存活和增强的免疫应答。 激活识别非靶向抗原的内源性T细胞（抗原扩散）。 我们的ETC（内源性T细胞疗法）ACT方法是开创一种使用外周血T细胞的策略， 血液是T细胞的来源。使用IL-21引发的组合（以富集中央记忆类型T 细胞）和四聚体引导的细胞分选，我们可以常规地从肿瘤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- 型特异性T细胞具有确定的特异性和高复制能力，如几个 先前的研究表明，在1- 10%的频率下， 持久的临床反应。我们提出了一项针对COL 6A 3和VCY的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 确定了与PD 1阻断联合的扩展队列。

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.