Adoptive T Cell Therapy for Pancreatic Cancer

胰腺癌今年将导致美国超过4.4万人死亡，目前已成为美国第三大癌症 癌症死亡的主要原因；在过去的40年里，这种疾病的存活率没有改变。虽然 免疫检查点抑制剂已成为治疗高度恶性肿瘤的有效方法。 突变负担，这不是胰腺癌的情况，因为它缺乏显著的内源性 肿瘤反应性T细胞群。过继转移抗原特异性T细胞将提供效应器 用于免疫检查点抑制的底物，我们推断这样的组合策略将是 令人向往。在这项提案中，我们解决了推进采用蜂窝技术的两个主要挑战 胰腺癌的治疗(ACT)：1.缺乏已证实的胰腺癌免疫原靶点 以及2.一种快速部署针对这些抗原的抗原特异性细胞疗法的方法。在这 我们计划以肿瘤细胞相关靶抗原(VCY)和肿瘤间质相关抗原为靶点 靶基因(COL6A3)，既是高度流行的(70%的肿瘤)，也是高度免疫原性的。我们的科学研究 前提是解决胰腺癌中缺乏肿瘤反应性T细胞的策略，在这种情况下 突变负担和免疫原性明显较低，这将是可取的，并可以通过 识别胰腺癌相关抗原的肿瘤反应性T细胞过继转移。 过继细胞疗法(ACT)是一种很有前途的免疫疗法，它涉及到体外分离 并扩增抗原特异性T细胞以供输注。基于这样的前提，战略延伸 转移的T细胞在体内的持久性和诱导抗原扩散将导致改善 ACT后的临床反应，我们假设长期中央记忆的过继转移 T型T细胞联合PD1阻断可延长体内存活时间并增强 识别非靶向抗原的内源性T细胞的激活(抗原传播)。 我们对ACT的ETC(内源性T细胞治疗)方法是开创一种使用外周血淋巴细胞的策略 血液是T细胞的来源。使用IL-21的组合启动(以丰富中央记忆类型T 细胞)和四聚体引导的细胞分选，我们可以常规地从 外周血液(1：100,000)，并将其扩展到200亿个统一定义的中央内存- 具有明确的特异性和高复制能力的类型特异性T细胞，如几个 先前的研究表明，在体内持续数月的频率为1%-10% 持久的临床反应。我们提出了一项针对COL6A3和VCY的IB期试验，用于治疗 难治性胰腺癌，在剂量递增队列中第一次，当剂量已经 已确定，扩展队列与PD1封锁相结合。

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.