Project 2: Intratumoral PDT Induces PDP-based Enhancement of PD-1 Inhibition in Pancreatic Carcinoma

摘要-项目2 胰腺导管腺癌（PDAC）是最致命的恶性肿瘤之一，通常出现在 晚期治疗这些癌症的进展一直很缓慢，而且只产生了非常有限的效果 提高生存率。为数不多的积极进展之一是免疫检查点抑制剂的使用 (ICI)PDAC伴微卫星不稳定性（MSI）。不幸的是，MSI在 这些癌症。该项目的目标是通过以下方式将ICI的使用扩展到大多数PDAC肿瘤 通过原发性肿瘤的光动力引发（PDP）刺激免疫系统，使用静脉内 光敏剂维替泊芬，其通过经由光纤递送的光激活，所述光纤通过细纤维递送。 在内窥镜超声或CT引导下穿刺肿瘤。这将启动PDP，该过程 激活免疫细胞募集到肿瘤中，并训练T细胞对肿瘤产生反应。 原发性PDAC以及外周转移。我们有一个肺转移瘤复发的病人 在原发性癌症的PDP治疗后，没有任何额外的化疗或免疫治疗。在 此外，我们能够显示外周血中肿瘤导向T细胞（对ICI有反应）的增加， 另一名患者在我们给予PDP治疗胰腺癌后72小时的血液。在项目2中，我们 进行II期研究，使用PDP（Veteporfin和红光）联合治疗，随后进行ICI （派姆单抗）。目的1将在25例局部晚期或晚期乳腺癌患者中评估这种联合治疗。 晚期胰腺癌（寡转移），由于其增加总体和疾病特异性存活的能力， 产生原发肿瘤的坏死和转移性疾病的消退;我们还将监测任何 毒性PDP的剂量测定将基于CT扫描上肿瘤的血管灌注以及 荧光测量从颊粘膜（与核心C），避免直接测量在 以前发现不可靠的肿瘤。目标2将使用PDP辐射指数（在残差中找到 PDP后的肿瘤）来预测对ICI的反应。该指数是基于肿瘤特征的变化， 反映在肿瘤异质性中的炎性浸润程度。我们还将使用高光谱 荧光显微内窥镜检查用于评估来自转移性疾病淋巴结的淋巴细胞 参与（核心B），以确定这是否与流式细胞术发现的亚群相关。最后， 目的3：观察PDP对PDAC患者外周血淋巴细胞免疫功能的影响 患者，以确定这些变化是否与PDP后淋巴细胞亚群的变化相关 PDP后在已知免疫敏感的皮肤肿瘤（鳞状细胞癌）中观察到（项目1） 和那些不是（基底细胞癌）。最后，在一组5名患者中，我们将对大转移性肿瘤进行采样， 淋巴结PDP后3天，以评估免疫细胞的变化，以确定是否ICI 针对肿瘤的响应性T细胞将增加。

ABSTRACT - Project 2 Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies and typically presents at advanced stages. Progress in treating these cancers has been slow and has produced only very modest increases in survival. One of the few positive developments has been the use of immune checkpoint inhibitors (ICI) in the setting of PDAC with microsatellite instability (MSI). Unfortunately, MSI is uncommonly found in these cancers. The goal of this project is to expand the usage of ICI to the majority of PDAC tumors by stimulating the immune system via photodynamic priming (PDP) of the primary tumor, using the intravenous photosensitizer Verteporfin which is activated by light delivered via an optical fiber delivered though a fine needle into the tumor under endoscopic ultrasound or CT guidance. This initiates PDP, a process that activates immune cell recruitment into the tumor and educates T-cells to mount a response against the primary PDAC as well as peripheral metastasis. We had a patient in whom a pulmonary metastasis regressed after PDP treatment of the primary cancer, without any additional chemotherapy or immunotherapy. In addition, we were able to show an increase in tumor-directed T cells (responsive to ICI) in the peripheral blood of another patient 72 hours after we administered PDP for pancreatic cancer. In Project 2, we will perform a Phase II study using combination therapy with PDP (Veteporfin and red light) followed by ICI (pembrolizumab). Aim 1 will assess this combination treatment in 25 patients with locally advanced or advanced pancreatic cancer (oligometastasis), for its ability to increase overall and disease specific survival, produce necrosis of the primary tumor and regression of metastatic disease; we will also monitor for any toxicities. Dosimetry for PDP will be based on vascular perfusion of the tumor on CT scans as well as fluorescence measurements from the buccal mucosa (with Core C), avoiding direct measurements in the tumor which were found to be unreliable previously. Aim 2 will use a PDP radiometric index (found in residual tumor after PDP) to predict response to ICI. The index is based on changes in tumor characteristics related to the degree of inflammatory infiltrate that is reflected in tumor heterogenity. We will also use hyperspectral fluorescence microendoscopy to evaluate lymphocytes from lymph nodes with metastatic disease involvement (Core B), to determine if this correlates with the subpopulations found by flow cytometry. Finally, Aim 3 will focus on PDP-stimulated immune cell changes in peripheral blood lymphocytes of our PDAC patients, to determine if these changes correlate with post-PDP changes in lymphocyte sub-populations observed after PDP in skin tumors (Project 1) that are known to be immune sensitive (squamous cell cancer) and those that are not (basal cell cancer). Finally, in a group of 5 patients we will be sampling large metastatic lymph nodes 3 days after PDP to assess the changes in immune cells, in order to determine whether ICI responsive tumor directed T-cells will increase.