Photodynamic Priming of Cancer and Image-guidance for Optimal Immune Response

总体概述 对于最佳的癌症治疗，机械互补和定向的组合方法 在非重叠的分子靶标是必需的。从战略上讲，应该选择组合， 第一次治疗为第二次治疗准备肿瘤。根据我们自己的调查结果， 胰腺癌（PDAC）和非黑色素瘤皮肤癌（NMSC）的光动力疗法（PDT）， 沿着免疫治疗的最新进展，我们假设损伤相关过程触发了 可以形成光动力引发（PDP）的基础，以促进基于免疫的组合 疗法PDP诱导免疫原性细胞死亡，增强肿瘤浸润淋巴细胞（TIL）的流入， 使肿瘤微环境对免疫检查点抑制（ICI）敏感。我们将捕捉PDP效应 设计一种非经验性的PDT-ICI联合治疗方法。我们将在这方面得到我们的帮助。 高光谱共聚焦成像的最新创新，可以同时监测6种生物标志物 携带肿瘤的动物，并允许定量TIL亚群沿着PD 1/PD-L1表达变化。 我们认为，当免疫学上的“冷”肿瘤首先转化为“热”肿瘤时，ICI将是最有益的。 通过PDP治疗治疗肿瘤，从而使所需的ICI剂量最小化并降低毒性。我们的计划有3 研究项目和2个科学核心，加上一个行政核心。项目1和2主要是临床的 而项目3完全是临床前的，推动形成假设基础的基本发现。 项目1介绍了一种用于治疗NMSC的双启动策略;首先对肿瘤进行药物治疗， 逻辑上与5-氟尿嘧啶或维生素D一起使用以增强PDT引发，这反过来又增加了ICI的功效。 项目2关注对化疗无反应的胰腺癌患者的PDP。PDT是 在内镜超声（EUS）引导下输送，ICI输送的时间由来自 项目3和检查一些患者转移淋巴结中的TIL亚群。项目3 深入研究了PDAC小鼠模型和患者源性免疫类器官中TIL的PDP诱导 (PDIO的）。核心至关重要。核心B将协助项目1和3进行临床前高分辨率成像 模型和PDIO，核心C将支持所有具有剂量测定技术的项目，以监测肿瘤治疗 包括放射组学，以收集PDAC患者CT扫描的新信息。我们 提出了PDT与免疫检查点抑制（ICI）的新组合，如果以合理的方式进行 通过光学成像来监测细胞水平和真实的时间的分子反应， 减少ICI治疗的主要障碍（缺乏有效的免疫细胞浸润到肿瘤中）。影响和 相关性：该计划积极影响两种癌症的治疗，PDAC和NMSC， 在高死亡率/发病率和高发病率范围的两端。这两种癌症都给社会带来了沉重的负担。 成本和痛苦的负担。这项工作的发现也可以转化为其他类型的癌症。

OVERALL PROGRAM SUMMARY For optimal cancer therapy, combination approaches that are mechanistically complementary and directed at non-overlapping molecular targets are needed. Strategically, combinations should be selected such that the first treatment primes the tumor for the second treatment. Building upon our own findings and work on photodynamic therapy (PDT) in pancreatic adenocarcinoma (PDAC) and nonmelanoma skin cancer (NMSC), along with recent advances in immunotherapy, we hypothesize that the damage-related processes triggered by PDT can form the basis for Photodynamic Priming (PDP) to promote an immune-based combination therapy. PDP induces immunogenic cell death, enhances influx of tumor infiltrating lymphocytes (TILs), and sensitizes the tumor microenvironment to immune checkpoint inhibition (ICI). We will capture the PDP effect to design a non-empiric approach for PDT-ICI combination therapy. We will be helped in this effort by our recent innovation of hyperspectral confocal imaging that can monitor 6 biomarkers simultaneously in live tumor bearing animals, and allow quantification of TIL subsets along with PD1/PD-L1 expression changes. We posit that ICI will be most beneficial when immunologically “cold” tumors can first be converted to “hot” tumors via PDP treatment, thereby minimizing the ICI dose required and reducing toxicity. Our Program has 3 Research Projects and 2 scientific Cores, plus an Administrative Core. Projects 1 and 2 are largely clinical while Project 3 is exclusively pre-clinical, driving fundamental findings that form the basis of the hypothesis. Project 1 introduces a double-priming strategy for the treatment of NMSC; the tumor is first treated pharmaco- logically with 5-fluorouracil or Vitamin D to enhance PDT priming, which in turn increases the efficacy of ICI. Project 2 focuses on PDP in pancreatic cancer patients who are unresponsive to chemotherapy. PDT is delivered under endoscopic ultrasound (EUS) guidance, and timing of ICI delivery is informed by findings from Project 3 and by examining subpopulations of TILs in metastatic lymph nodes in some patients. Project 3 looks in-depth at PDP induction of TILs in a PDAC murine model, and in patient-derived immune organoids (PDIO’s). Cores are critical. Core B will assist Projects 1 and 3 with high resolution imaging in preclinical models and PDIOs, and Core C will support all projects with dosimetry techniques to monitor tumor treatment response, including radiomics to garner new information from CT scans in PDAC patients. We propose t h a t new combinations o f PDT with immune checkpoint inhibition (ICI), if done in a rational way that is informed by optical imaging to monitor molecular responses at the cellular level and in real time, will reduce a major barrier to ICI therapy (the lack of effective immune cell infiltration into the tumor). Impact and Relevance: This program positively impacts the treatment of two cancers, PDAC and NMSC, at opposite ends of the spectrum of high mortality/morbidity and high incidence. Both cancers inflict a heavy societal burden of cost and suffering. Findings from this work could also be translatable to other types of cancer.