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

癌症的光动力引发和最佳免疫反应的图像引导

基本信息

批准号：
10494484
负责人：
Tayyaba Hasan
金额：
$ 127.49万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/10494484
关键词：
Animals Automobile Driving Behavior Biological Markers Budgets Categories Cells Clinical Clinical Research Clinical Trials Collaborations Combined Modality Therapy Custom Development Diagnostic Disease Dose Economic Burden Endoscopic Ultrasonography Endoscopy Environment Excision Fibroblasts Fluorouracil Future Human Image Imaging Device Immune Immune checkpoint inhibitor Immune response Immunocompetent Immunologic Monitoring Immunologics Immunotherapy Incidence Industry Infiltration Intelligence Knowledge Lead Learning Lesion Lymphocyte Subset Malignant Neoplasms Malignant neoplasm of pancreas Mediating Microsatellite Instability Modeling Molecular Molecular Target Monitor Morbidity - disease rate Mus Neoadjuvant Therapy Optics Organoids Outcome PD-1/PD-L1 PUVA Photochemotherapy Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pancreatic carcinoma Pathway interactions Patients Pattern Peer Review Permeability Pharmacology Pre-Clinical Model Process Prognosis Program Research Project Grants Proteins Publications Radiology Specialty Regimen Research Research Project Grants Skin Cancer Skin Carcinoma T-Cell Activation T-Lymphocyte Subsets Techniques Therapeutic Time Toxic effect Tumor Escape Tumor-Infiltrating Lymphocytes United States Verteporfin Visible Radiation Vitamin D Work X-Ray Computed Tomography anti-PD-1 base cancer imaging cancer therapy cancer type checkpoint inhibition chemotherapy clinical translation cohort confocal imaging conventional therapy cost cytotoxic design dosimetry high resolution imaging image guided immune checkpoint immunogenic cell death improved innovation lymph nodes mortality mouse model novel optical imaging pancreatic cancer model pancreatic cancer patients patient subsets pembrolizumab pre-clinical preclinical study programmed cell death protein 1 programs radiomics recruit response side effect success symposium tool treatment response treatment strategy tumor tumor microenvironment ultrasound

项目摘要

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.

项目总体总结