Project 3: Immune Checkpoint Inhibition Therapy Enhanced by Integrated Photodynamic Treatment and Image Guidance in Preclinical Models of Pancreatic Cancer

项目3：胰腺癌临床前模型中综合光动力治疗和图像引导增强免疫检查点抑制治疗

• 批准号: 10705154
• 负责人: Tayyaba Hasan
• 金额: $ 17.66万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705154
• 关键词: 3-Dimensional; Abscopal effect; Adverse effects; Animals; Area; Autologous; Bilateral; Biological Markers; Blinded; Blood Vessels; Categories; Cell Line; Cell Survival; Chemoresistance; Clinical; Collaborations; Combination Drug Therapy; Combined Modality Therapy; Data; Diameter; Dimensions; Disease; Dose; Eligibility Determination; FDA approved; Fine needle aspiration biopsy; Future; Generations; Goals; Heterogeneity; Human; Image; Immune; Immune response; Immunocompetent; Immunologic Monitoring; Immunologics; Immunotherapeutic agent; Immunotherapy; Intervention; KPC model; Light; Literature; Lymphocytic Infiltrate; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Metabolic; Microsatellite Instability; Modeling; Molecular Target; Monitor; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Organoids; Outcome; PD-1/PD-L1; PUVA Photochemotherapy; Pancreatic Ductal Adenocarcinoma; Pathologist; Patients; Performance; Peripheral Blood Mononuclear Cell; Permeability; Pharmaceutical Preparations; Phenotype; Photosensitizing Agents; Pre-Clinical Model; Process; Radiation; Radiology Specialty; Receptor Protein-Tyrosine Kinases; Refractory; Reporting; Research; Resolution; Study models; Survival Rate; Technology; Testing; Therapeutic; Time; Toxic effect; Treatment-related toxicity; Tumor Immunity; Tumor Volume; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Tyrosine Kinase Inhibitor; Validation; Verteporfin; Visualization; anti-PD-1; anti-PD-L1; anti-PD-L1 therapy; anti-PD1 therapy; anti-tumor immune response; cancer imaging; checkpoint inhibition; chemotherapy; cytokine; design; dosage; dosimetry; efficacy evaluation; functional status; high resolution imaging; image guided; imaging capabilities; imaging platform; imaging system; immune cell infiltrate; immune checkpoint blockade; immune resistance; immunogenic; immunogenic cell death; immunoregulation; in vivo; innovation; insight; migration; mouse model; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; pancreatic cancer model; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; patient population; pembrolizumab; pharmacologic; point of care; preclinical study; radioresistant; response; statistics; subcutaneous; success; synergism; therapy design; therapy outcome; three-dimensional modeling; tool; treatment response; treatment strategy; tumor; tumor growth; tumor microenvironment; validation studies

The statistics for pancreatic ductal adenocarcinoma (PDAC) remain dismal despite advances in combination chemotherapies. It is largely chemo and radiation resistant, and surgery, the only curative option, is available to only ~20% of patients. Immune checkpoint inhibition (ICI) has brought hope but in PDAC even the modest success (anti-PD1: Pembrolizumab) is limited to only 1-3% of patients displaying microsatellite instability. The majority of tumors lack the immune infiltration necessary for effective ICI. Based on our data and the literature, we hypothesize that Photodynamic Priming (PDP), a process that is a fallout of photodynamic therapy (PDT) and our main research focus, alters the tumor microenvironment to sensitize it to enhance ICI therapy. PDP induces immunogenic cell death and enhances tumor infiltrating lymphocyte (TIL) migration, augmented by PDP-induced higher tumor permeability.. We capture this priming effect for designing a non-empiric approach for a PDT-ICI combination. We are greatly helped in this by our recent innovation of hyperspectral imaging capable, for the first time, of monitoring 6 biomarkers simultaneously in live tumor bearing animals; it allows us to quantify TILs (and subsets) along with PD1/PD-L1 expression changes to generate an immunoscore (IS). We posit that ICI administration will be most beneficial when the tumor has been PDP-stimulated to be the “hottest” thus minimizing ICI dose and associated toxicities, similar to that observed for PDP-chemotherapy combinations. The hypothesis will be tested in 3 aims. Aim 1 will identify, in orthotopic murine tumors, PDP- dosimetry and optimal timing for IS modulation to establish the time for maximal benefits of anti-PD1 therapy (increased survival, decreased metastasis) and increased tolerability. Aim 2, informed by aim 1, will use both orthotopic and a bilateral subcutaneous PDAC murine model to determine abscopal effects of PDP-ICI therapy. A comparison of optimally timed, single dose ICI therapy with multiple dosages along with a comparison of single immune checkpoint blockade (anti-PD1) with dual blockade (anti-PD1/anti-PD-L1) will also be established. Aim 3 will utilize patient derived tumor immune organoids (PDIO), to recapitulate heterogeneity and evaluate the combination therapy outcomes. PDP induced IS will inform optimally timed anti-PD1/anti-PD-L1 therapy guidance for PDIOs. Relevance and Impact 1) it sensitizes non-immune responsive tumors to responsive ones and expands the eligible PDAC patients (currently only at 3%). 2) A non-empiric approach is introduced. 3) Combined with imaging-enabled dose reduction of anti-PD1 it reduces toxicities of immune drugs as reported with chemotherapy and receptor tyrosine kinase inhibitors. 4) It provides a broad imaging platform for in vivo real-time multiple-marker information at cellular resolution and serves as a general point-of-care tool by enabling simultaneous visualization of several molecular targets (e.g., tumor immune cell phenotypes and cytokines/stromal/metabolic signatures) for designing new therapies for many other diseases, and with potential to expand the use of fine needle aspirate biopsy for PDAC ICI dosimetry.

胰腺导管腺癌（PDAC）的统计数据仍然令人沮丧，尽管联合治疗取得了进展。 化疗它在很大程度上是耐化疗和辐射的，手术是唯一的治疗选择 只有约20%的患者。免疫检查点抑制（ICI）带来了希望，但在PDAC中， 成功（抗PD 1：Pembrolizumab）仅限于1-3%显示微卫星不稳定性的患者。的 大多数肿瘤缺乏有效ICI所必需的免疫浸润。根据我们的数据和文献， 我们假设，光动力学引发（PDP），一个过程，是光动力学治疗（PDT）的一个附带结果， 和我们的主要研究重点，改变肿瘤微环境，使其敏感，以加强ICI治疗。PDP 诱导免疫原性细胞死亡并增强肿瘤浸润淋巴细胞（TIL）迁移， PDP诱导的更高的肿瘤渗透性我们捕捉这种启动效应，设计一个非经验的方法， 进行PDT和ICI联合治疗我们最近的高光谱成像技术的创新极大地帮助了我们 首次能够在活的荷瘤动物中同时监测6种生物标志物;它使我们能够 以量化TIL（和子集）沿着PD 1/PD-L1表达变化，从而生成免疫评分（IS）。 我们认为，当肿瘤已经被PDP刺激到最大程度时，ICI给药将是最有益的。 “最热”，从而使ICI剂量和相关毒性最小化，与PDP化疗观察到的相似 组合。该假设将在3个目标中进行检验。目的1将在原位小鼠肿瘤中鉴定PDP-1。 IS调节的剂量测定和最佳时机，以确定抗PD 1治疗的最大获益时间 （增加的存活率，减少的转移）和增加的耐受性。目标2受目标1的启发， 原位和双侧皮下PDAC小鼠模型，以确定PDP-ICI的远端效应 疗法比较最佳时间的单剂量ICI治疗与多剂量沿着的 单免疫检查点阻断（抗PD 1）与双重阻断（抗PD 1/抗PD-L1）的比较将 也要建立。目标3将利用患者源性肿瘤免疫类器官（PDIO），以概括 异质性，并评估联合治疗的结果。PDP诱导的IS将通知最佳时间 PDIO的抗PD 1/抗PD-L1治疗指导。相关性和影响1）它使非免疫者敏感 将有效肿瘤转化为有效肿瘤，并扩大合格PDAC患者（目前仅为3%）。2)一 非经验方法被引入。3)结合成像使能的抗PD 1剂量降低， 化疗和受体酪氨酸激酶抑制剂报告的免疫药物毒性。4)它提供 一个广泛的成像平台，用于在细胞分辨率下的体内实时多标记信息， 通过能够同时可视化几个分子靶（例如，肿瘤 免疫细胞表型和细胞因子/基质/代谢特征），用于为许多 其他疾病，并有可能扩大使用细针抽吸活检PDAC ICI剂量测定。