Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging cancers to treat. For patients with advanced and metastatic disease, chemotherapy has yielded only modest incremental benefits, which are not durable. Immunotherapy has revolutionized the treatment of other solid tumors by leading to cures where none existed only a decade ago, yet it has made few inroads with PDAC. A host of trials with promising preclinical data have failed, except for in a small minority of patients with selected biomarkers. There is, however, a glimmer of hope, which we seek to cultivate. In this review, we discuss recent advances in the understanding of the uniquely immunosuppressive tumor microenvironment (TME) in PDAC, learnings from completed trials of checkpoint inhibitors, TME modifiers, cellular and vaccine therapies, oncolytic viruses, and other novel approaches. We go on to discuss our expectations for improved preclinical models of immunotherapy in PDAC, new approaches to modifying the TME including the myeloid compartment, and emerging biomarkers to better select patients who may benefit from immunotherapy. We also discuss improvements in clinical trial design specific to immunotherapy that will help us better measure success when we find it. Finally, we discuss the urgent imperative to better design and execute bold, but rational, combination trials of novel agents designed to cure patients with PDAC.

中文翻译：

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胰腺癌免疫治疗的事实和希望


胰腺导管腺癌（PDAC）仍然是最具挑战性的癌症之一。对于患有晚期和转移性疾病的患者，化疗仅产生了有限的增量益处，而且这种益处并不持久。免疫疗法彻底改变了其他实体瘤的治疗方法，带来了十年前还没有的治疗方法，但它在 PDAC 方面却几乎没有取得进展。除了少数具有选定生物标志物的患者外，许多具有前景的临床前数据的试验都失败了。然而，我们仍努力培养一线希望。在这篇综述中，我们讨论了对 PDAC 中独特的免疫抑制肿瘤微环境 (TME) 的理解的最新进展，从检查点抑制剂、TME 修饰剂、细胞和疫苗疗法、溶瘤病毒和其他新方法的已完成试验中获得的经验教训。我们继续讨论我们对改进 PDAC 免疫治疗临床前模型的期望、修改 TME（包括骨髓区室）的新方法以及新兴生物标志物，以更好地选择可能受益于免疫治疗的患者。我们还讨论了针对免疫疗法的临床试验设计的改进，这将有助于我们在发现成功时更好地衡量成功。最后，我们讨论了更好地设计和执行旨在治愈 PDAC 患者的新型药物的大胆但合理的联合试验的迫切需要。