Potentiating a systemic antitumor response by interstitial localized ablative immunotherapy to synergize with immune checkpoint therapy for metastatic pancreatic tumors

项目摘要 胰腺癌（PC）是最致命的疾病之一。根据2021年美国癌症统计数据， 的PC患者被诊断为晚期疾病，伴有远处转移（50%）或局部浸润 (30%），五年生存率分别为3%和13%。在大多数情况下，特别是在 阶段，PC是不可切除的，药物不可渗透的，免疫抑制的，和高度转移性的。 传统疗法，如手术、放疗和化疗，在很大程度上是无效的。连 先进的免疫疗法，如免疫检查点疗法（ICT），只能取得有限的成功，由于 免疫抑制肿瘤微环境（TME）中缺乏T细胞。我们开发了一个本地化的 消融性免疫治疗（LAIT），结合局部光热治疗（PTT）和局部给药 免疫刺激剂。在我们的临床前研究和初步临床试验中，LAIT已被证明能够 以消除治疗的肿瘤和根除未治疗的远处转移。具体来说，PTT破坏肿瘤细胞 由于靶组织的光吸收，导致免疫原性细胞死亡和肿瘤抗原的释放。 局部施用的免疫刺激剂与释放的肿瘤抗原组合，诱导肿瘤特异性免疫应答。 免疫应答，特别是TME内T细胞的浸润、活化和增殖。然而，在这方面， 迄今为止，LAIT主要应用于表面肿瘤的非侵入性模式，如黑色素瘤和乳腺癌 癌在这个项目中，我们将使用间质LAIT（iLAIT）治疗原位小鼠胰腺肿瘤， 结合ICT。我们假设1）iLAIT重塑TME并诱导抗肿瘤免疫， 与ICT协同作用以提高PC的治疗效果;和2）新型iLAIT-ICT的机制 联合治疗涉及肿瘤细胞和免疫细胞之间的协调相互作用，以克服免疫缺陷。 免疫抑制性TME。为了验证这些假设，我们计划使用两个胰腺癌细胞来实现以下目标。 小鼠肿瘤模型：1）优化iLAIT并确定其在治疗转移性胰腺肿瘤中的功效; 2)确定iLAIT在逆转免疫抑制性TME和诱导全身性抗肿瘤作用中的作用 次级免疫器官中的反应;和3）确定iLAIT和ICT的协同作用，特别是 治疗胰腺肿瘤的功效和诱导的肿瘤特异性长期免疫。这个项目 临床相关性高。该项目的成功完成将证明 iLAIT-ICT，为其临床应用铺平了道路，并进行了微小修改（消融剂量和 免疫刺激），对于晚期，转移性PC患者，谁面临严重有限的选择。而且 了解iLAIT-ICT调节的，肿瘤细胞之间时空协调的相互作用， 免疫细胞将来可用于设计各种转移性癌症的新治疗方法。

Project Summary Pancreatic cancer (PC) is one of the deadliest diseases. Based on the 2021 U.S. cancer statistics, the majority of PC patients are diagnosed with advanced-stage disease, either with distant metastasis (50%) or local invasion (30%), resulting in a five-year survival rate of 3% and 13%, respectively. In most cases, particularly at the late stages, PC is unresectable, non-permeable to drugs, immunologically suppressive, and highly metastatic. Conventional therapies, such as surgery, radiation, and chemotherapy, are largely ineffective. Even the advanced immunotherapies, such as immune checkpoint therapy (ICT), can only achieve limited success, due to the lack of T cells in the immunosuppressive tumor microenvironment (TME). We developed a localized ablative immunotherapy (LAIT), which combines local photothermal therapy (PTT) and local administration of immunostimulants. In our pre-clinical studies and preliminary clinical trials, LAIT has been shown to be able to eliminate treated tumors and eradicate untreated distant metastases. Specifically, PTT destroys tumor cells due to light absorption by the target tissue, leading to immunogenic cell death and the release of tumor antigens. The locally administered immunostimulants, combined with released tumor antigens, induces tumor-specific immune responses, particularly the infiltration, activation, and proliferation of T cells within the TME. However, so far LAIT has been applied mostly in non-invasive mode for surface tumors, such as melanoma and breast cancer. In this project, we will use interstitial LAIT (iLAIT) to treat orthotopic murine pancreatic tumors, in combination with ICT. We hypothesize 1) iLAIT remodels the TME and induces antitumor immunity that synergizes with ICT to improve therapeutic efficacy for PC; and 2) the mechanism of the novel iLAIT-ICT combination involves a coordinated interplay between tumor cells and immune cells to overcome the immunosuppressive TME. To test these hypotheses, we plan to achieve the following aims using two pancreatic tumor models in mice: 1) to optimize iLAIT and to determine its efficacy in treating metastatic pancreatic tumors; 2) to determine the effects of iLAIT in reversing immunosuppressive TME and inducing systemic antitumor responses in secondary immune organs; and 3) to determine the synergistic effects of iLAIT and ICT, specifically the efficacy in treating pancreatic tumors and the induced tumor-specific, long-term immunity. This project has high clinical relevance. The successful completion of this project will demonstrate the therapeutic efficacy of iLAIT-ICT, paving the way for its clinical applications, with minor modifications (doses of ablation and immunostimulation), for late-stage, metastatic PC patients, who face severely limited options. Furthermore, the understanding of the iLAIT-ICT-regulated, spatiotemporally coordinated interplay between tumor cells and immune cells can be used to design new therapeutic approaches for a variety of metastatic cancers in the future.