Optimal Pairing of Chemotherapy with Immunotherapy for Pancreatic Cancer

最近的证据表明，人胰腺导管腺癌（PDA）易受免疫抑制， 承认和拒绝。这提出了确定PDA免疫治疗策略的挑战， 不需要过度的劳动强度，可以持续延长生存期，理想情况下可以治愈。在我们努力中 为了开发有效的现成的针对PDA的免疫疗法，我们发现重复给药 环磷酰胺（CY）与TLR激动剂（TLRa）交替使用在治疗上与TLR激动剂（TLRa）相同或更有效， CY和T细胞过继疗法的经典协同组合。现成CY+TLRa治疗 比过继疗法劳动强度小得多，耐受性好，并且通常足以治愈同基因 晚期PDA肿瘤的野生型小鼠。值得注意的是，CY+TLRa的治疗效果被完全废除， 耗尽宿主CD 4+和CD 8 + T细胞和NK细胞，表明CY+TLRa成功地维持了免疫应答。 内源性抗肿瘤免疫应答，即使在没有过继治疗或疫苗操作的情况下。 另一个独特的治疗特征是CY+TLRa将反弹的髓样祖细胞转化为细胞因子的能力。 杀肿瘤巨噬细胞，从而防止肿瘤将其分化为骨髓源性巨噬细胞。 抑制细胞我们的具体目标是（1）充分阐明CY+TLRa治疗的机制， 对小鼠PDA模型治疗有效，以最大化可翻译性;（2）进行I-II期 使用新型TLR 8激动剂的临床试验将迅速评估PDA患者的这种策略， VentiRx-2337;以及（3）完成能够引发T细胞应答的疫苗策略的开发 以及逆转T细胞对MUC 1的耐受性，其被>90%的人PDA MUC 1超表达。 这将纳入CY+TLRa策略，目标是统一提供这种治疗 对PDA有效。

Recent evidence indicates that human pancreatic ductal adenocarcinoma (PDA) is vulnerable to immune recognition and rejection. This raises the challenge of identifying immunotherapy strategies for PDA that are not excessively labor intensive, that consistently prolong survival, and that ideally are curative. In our effort to develop effective off-the-shelf immunotherapy against PDA, we discovered that repetitive administration of cyclophosphamide (CY) alternating with TLR agonists (TLRa) is therapeutically as or more effective than the classically synergistic combination of CY and T cell adoptive therapy. Off-the-shelf CY+TLRa treatment is much less labor intensive than adoptive therapy, is well tolerated, and is often sufficient to cure syngeneic wildtype mice of advanced PDA tumors. Remarkably, CY+TLRa¿s therapeutic efficacy is fully abrogated by depleting host CD4+ and CD8+ T cells and NK cells, indicating that CY+TLRa successfully maintains an endogenous anti-tumor immune response even in the absence of adoptive therapy or vaccine maneuvers. An additional unique therapeutic feature is CY+TLRa's ability to convert rebounding myeloid progenitors into tumoricidal macrophages, thereby preventing tumors from differentiating them into myeloid-derived suppressor cells. Our Specific Aims are (1) to fully delineate the mechanism by which CY+TLRa treatment is therapeutically effective against mouse PDA models, to maximize translatability; (2) to perform Phase I-II clinical trials which will promptly evaluate this strategy in PDA patients, using the novel TLR8 agonist VentiRx-2337; and (3) to complete development of a vaccine strategy capable of priming T cell responses as well as reversing T cell tolerance to MUC1, which is hyperexpressed by >90% of human PDA MUC1. This will be incorporated in the CY+TLRa strategy with the goal of rendering this treatment uniformly effective for PDA.