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

总体计划摘要 对于最佳癌症治疗，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，应该选择这样的组合： 第一次治疗为第二次治疗肿瘤做好了准备。以我们自己的发现和工作为基础 光动力疗法在胰腺癌(PDAC)和非黑色素瘤皮肤癌(NMSC)中的应用 随着免疫治疗的最新进展，我们假设与损伤相关的过程引发了 可以形成光动力引发(PDP)的基础，以促进基于免疫的结合 心理治疗。PDP诱导免疫原性细胞死亡，增加肿瘤浸润性淋巴细胞(TIL)的内流，以及 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 目的：设计一种非经验性的PDT-ICI联合治疗方法。我们将在这一努力中得到我们的帮助 高光谱共聚焦成像的最新创新，可在活体内同时监测6个生物标志物 并允许随着PD1/PD-L1表达的变化而对TIL亚群进行量化。 我们假设，当免疫“冷”瘤首先转化为“热”瘤时，ICI将是最有益的。 通过PDP治疗肿瘤，从而将所需的ICI剂量降至最低，并减少毒性。我们的节目有3个 研究项目和2个科学核心，外加一个行政核心。项目1和2主要是临床项目 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介绍了治疗NMSC的双引爆策略；肿瘤首先用药物治疗- 合理地使用5-氟尿嘧啶或维生素D来加强PDT的启动，这反过来又增加了ICI的疗效。 项目2重点研究对化疗无效的胰腺癌患者的PDP。光动力疗法是 在内窥镜超声(EUS)指导下交付，ICI交付的时间由以下发现提供信息 项目3，并通过检测一些患者的转移性淋巴结中的TIL亚群。项目3 在PDAC小鼠模型和患者来源的免疫器官中，深入观察PDP对TIL的诱导 (PDIO的)。核心是至关重要的。核心B将协助项目1和3在临床前进行高分辨率成像 模型和PDIO，以及核心C将支持所有具有剂量学技术的项目，以监测肿瘤治疗 反应，包括放射组学，以从PDAC患者的CT扫描中获得新的信息。我们 提出一种新的PDT与免疫检查点抑制(ICI)的组合，如果以合理的方式进行 这是通过光学成像来实时监测细胞水平上的分子反应，将 减少ICI治疗的一个主要障碍(缺乏有效的免疫细胞对肿瘤的渗透)。影响和 相关性：该计划对PDAC和NMSC这两种癌症的治疗产生了积极的影响 高死亡率/发病率和高发病率的两端。这两种癌症都给社会造成了沉重的社会负担 代价和痛苦的负担。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.