Fractionated photoimmunotherapy to harness low-dose immunostimulation in ovarian cancer

分段光免疫疗法利用低剂量免疫刺激治疗卵巢癌

基本信息

批准号：
10662778
负责人：
Heiko Enderling
金额：
$ 52.93万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662778
关键词：
3-Dimensional Abdominal Cavity Address Antibodies Biopsy Calibration Cancer Patient Cell surface Cells Chemicals Clinical Clinical Data Clinical Trials Coculture Techniques Combined Modality Therapy Complement Complex Custom Cytotoxic Chemotherapy Cytotoxic T-Lymphocytes Data Dendritic Cells Dependence Development Disease Distal Dose Dose Fractionation Epidermal Growth Factor Receptor Epithelial ovarian cancer Equilibrium Evolution Fluorescence Foundations Fractionation Funding Goals Greater sac of peritoneum Head and Neck Cancer Image Immune Immune checkpoint inhibitor Immune response Immune system Immunity Immunocompetent Immunologic Stimulation Immunologics Immunooncology Immunotherapy In Vitro Infiltration Intestines Light Link Malignant neoplasm of lung Malignant neoplasm of ovary Mathematics Measures Modality Modeling Molecular Molecular Target Monitor Newly Diagnosed Oncology Operative Surgical Procedures Outcome PUVA Photochemotherapy Paclitaxel Pathologic Patient-Focused Outcomes Patients Phase II Clinical Trials Photochemistry Photosensitizing Agents Phototherapy Phototoxicity Proliferating Protocols documentation Recurrence Regimen Site Skin Cancer Survival Rate T-Lymphocyte Testing Therapeutic Time Training Tumor Debulking Tumor Immunity Tumor-infiltrating immune cells Validation adaptive immune response alternative treatment anti-PD-1 anti-PD1 therapy cancer cell cancer infiltrating T cells cancer therapy checkpoint inhibition chemotherapy control theory cytotoxic cytotoxicity design dosimetry effector T cell experimental study image guided immunogenic cell death immunoregulation improved in silico in vivo in vivo imaging individualized medicine innovation mathematical methods mathematical model microendoscopy mouse model neoplastic cell novel personalized medicine photoimmunotherapy physical science pre-clinical preservation prospective responders and non-responders response simulation three dimensional cell culture time use treatment response tumor tumor-immune system interactions

项目摘要

PROJECT SUMMARY The survival of advanced or recurrent epithelial ovarian cancer (EOC) remains dismal due in part to the complex tumor–immune microenvironment (TIME). The presence of tumor-infiltrating T cells correlates with improved patient outcome in advanced EOC, yet checkpoint inhibitor immunotherapy has generally shown poor efficacy against EOC in clinical trials. A major challenge is the low number of T cells compared to EOC cells in the tumor that establish an immune-suppressive TIME. Tumor-targeted, cell-activatable photoimmunotherapy (taPIT, a near infrared phototherapy) may provide an alternative treatment approach that selectively destroys EOC cells expressing cell-surface epidermal growth factor receptor (EGFR) while enhancing the preservation of tumor infiltrating immune cells salient to an adaptive immune response (e.g., local cytotoxic T cells and dendritic cells). While photoimmunotherapy is not new, this is the first exploration of taPIT dose fractionation to selective eradicate EOC while stimulating immune cells at lower doses and preferentially sparing immune cells at higher doses. Based on our rich preliminary data, we propose that mathematical modeling-informed taPIT serves as a new paradigm for combined cytotoxic therapy and immunotherapy in metastatic EOC. Our overall goal is a novel experimental, simulation- and image-guided approach for utilizing the local selectivity of taPIT to prime “cold” TIME’s for immune checkpoint inhibition. This proposal contributes an innovative physical sciences approach to cancer therapy integrating mathematical modeling with a 3D culture model of the TIME and in vivo imaging experiments in immunocompetent mouse models of EOC, including in silico immuno-oncology modeling to optimize TIME composition-specific therapy; fractionated taPIT dosimetry to reduce the EOC cell burden relative to effector T cells and dendritic cells within the TIME; and, in vivo multiplexed fluorescence microendoscopy to interrogate the TIME of metastatic EOC within the peritoneal cavity. The unique ability to image micronodular disease will enable parameterizing a mathematical model with pre-treatment conditions and dynamic in vivo responses to therapy as a basis for the quantitative design of custom-tailored therapies. Our aims are (1) to train an in silico model by correlating clinical pre-treatment EOC TIME compositions with pathological anti-PD1 response; (2) to derive optimal fractionated taPIT protocols that shift “cold” to anti-PD1-sensitive “hot” TIME in vitro, and (3) to prime the TIME for anti-PD1 therapy in vivo. The concepts introduced here will ultimately enable taPIT–anti-PD1 therapy dosimetry that synergistically stimulates both local and distal immune-enhancing effects to impact disease sites missed by near infrared light, in combination with frontline surgical tumor debulking and systemic chemotherapy. The approaches developed here are translatable to other tumor sites that can be treated with taPIT, including head and neck cancers, skin cancers, and lung cancers.

项目概要晚期或复发性上皮性卵巢癌（EOC）的生存率仍然很低，部分原因是复杂的肿瘤免疫微环境 (TIME) 与肿瘤浸润 T 细胞的存在相关。改善晚期 EOC 患者的预后，但检查点抑制剂免疫疗法普遍显示临床试验中针对 EOC 的疗效不佳，一个主要挑战是与 EOC 相比，T 细胞数量较少。肿瘤中的细胞建立了肿瘤靶向的、细胞可激活的免疫抑制时间。光免疫疗法（taPIT，一种近红外光疗法）可能提供一种替代治疗方法选择性破坏表达细胞表面表皮生长因子受体 (EGFR) 的 EOC 细胞，同时增强对适应性免疫反应显着的肿瘤浸润免疫细胞的保存（例如，局部细胞毒性 T 细胞和树突状细胞）虽然光免疫疗法并不新鲜，但这是首次探索。 taPIT 剂量分级可选择性根除 EOC，同时以较低剂量刺激免疫细胞根据我们丰富的初步数据，我们建议在较高剂量下优先保护免疫细胞。基于数学模型的 taPIT 成为联合细胞毒治疗和我们的总体目标是一种新颖的实验、模拟和图像引导的免疫疗法。利用 taPIT 的局部选择性来启动“冷”TIME 进行免疫检查点抑制的方法。该提案为癌症治疗提供了一种创新的物理科学方法，整合了数学使用 TIME 的 3D 培养模型进行建模并在免疫活性小鼠中进行体内成像实验 EOC 模型，包括计算机免疫肿瘤学模型，以优化 TIME 组合物特异性治疗；分级 taPIT 剂量测定可减少 EOC 细胞相对于效应 T 细胞和树突状细胞的负担 TIME；以及体内多重荧光显微内窥镜检查转移性 EOC 的 TIME 腹膜腔内微结节疾病成像的独特能力将使参数化成为可能。以治疗前条件和体内动态治疗反应为基础的数学模型我们的目标是（1）通过关联来训练计算机模型。具有病理性抗PD1反应的临床预治疗EOC TIME组合物(2)以获得最佳效果；分次 taPIT 方案，在体外将“冷”时间转变为抗 PD1 敏感的“热”时间，以及 (3) 启动时间这里介绍的概念最终将使 taPIT-抗 PD1 疗法成为可能。协同刺激局部和远端免疫增强效应以影响疾病部位的剂量测定近红外光错过，结合前线肿瘤减灭手术和全身治疗这里开发的方法可以应用于其他可以治疗的肿瘤部位。 taPIT，包括头颈癌、皮肤癌和肺癌。