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，大多数 的PC患者被诊断为晚期疾病，要么有远处转移(50%)，要么有局部侵袭 (30%)，五年存活率分别为3%和13%。在大多数情况下，特别是在后期 PC分期，不能切除，对药物不能渗透，免疫抑制，高度转移。 传统的治疗方法，如手术、放疗和化疗，基本上是无效的。即使是那些 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， 与免疫抑制肿瘤微环境(TME)中T细胞缺乏有关。我们开发了一个本地化的 消融性免疫疗法(LAIT)，它结合了局部光热疗法(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，莱特已被证明能够 以消除已治疗的肿瘤并根除未经治疗的远处转移。具体地说，PTT可以破坏肿瘤细胞 由于光被靶组织吸收，导致免疫原性细胞死亡和肿瘤抗原的释放。 局部给药的免疫刺激剂与释放的肿瘤抗原相结合，诱导肿瘤特异性 免疫反应，尤其是T细胞在TME内的渗透、激活和增殖。然而， 到目前为止，激光治疗主要应用于黑色素瘤、乳腺等表面肿瘤的非侵入性治疗。 癌症。在这个项目中，我们将使用间质LAIT(ILAIT)来治疗原位小鼠胰腺肿瘤，在 与信息通信技术相结合。我们假设iLAIT重塑TME并诱导抗肿瘤免疫 与ICT协同改善PC的疗效；2)新型iLAIT-ICT的作用机制 联合涉及肿瘤细胞和免疫细胞之间的协调相互作用，以克服 免疫抑制药TME。为了验证这些假设，我们计划使用两个胰腺实现以下目标 小鼠肿瘤模型：1)优化iLAIT，观察其治疗胰腺转移瘤的疗效； 2)确定iLAIT逆转免疫抑制的TME和诱导全身抗肿瘤的作用 二次免疫器官的反应；以及3)确定iLAIT和ICT的协同效应，特别是 治疗胰腺肿瘤的疗效和诱导的肿瘤特异性、长期免疫。这个项目有 具有很高的临床相关性。这一项目的成功完成将证明 ILAIT-ICT，为其临床应用铺平道路，只需稍作修改(消融剂量和 免疫刺激)，适用于晚期转移性PC患者，他们面临的选择严重有限。此外， 理解iLAIT-ICT调节的肿瘤细胞和肿瘤细胞之间的时空协调相互作用 未来，免疫细胞可以用来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.