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SPORE in Skin Cancer

皮肤癌中的孢子

基本信息

批准号：
10480828
负责人：
RAVI K AMARAVADI
金额：
$ 219.42万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-03 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10480828
关键词：
Address Adjuvant Antibody Therapy Autophagocytosis BRAF gene Biological Biological Assay Biological Markers Blood CD8-Positive T-Lymphocytes Cancer Patient Clinical Clinical Investigator Clinical Management Clinical Trials Collaborations Combination immunotherapy Cutaneous Melanoma Cutaneous T-cell lymphoma Data Death Rate Dendritic Cells Development Disease Disease Progression Disease regression Dose Drug Design Early treatment Funding Genetic Genomics Immune Immune checkpoint inhibitor Immune response Immunologics Immunotherapeutic agent Immunotherapy Impairment In complete remission Institution Intervention Trial Knowledge Leadership Life Lymphoma cell Malignant Neoplasms Measurement Medicine Mentors Merkel cell carcinoma Mission Molecular Target Nature Neoadjuvant Therapy Nivolumab Operative Surgical Procedures Pathologic Pathway interactions Patients Peripheral Recording of previous events Refractory Regimen Reporting Research Research Design Research Personnel Resources Scientist Sensitivity and Specificity Series Skin Skin Cancer Skin Carcinoma T-Lymphocyte The Wistar Institute Therapeutic Toxic effect Translating Treatment-related toxicity Tumor Bank Tumor-associated macrophages Work anti-PD1 antibodies anti-PD1 therapy base bench to bedside career cell killing checkpoint inhibition cohort design disorder risk effective therapy exosome experience high risk improved industry partner inhibition of autophagy inhibitor innovation insight ipilimumab macrophage melanoma mutant neoplastic cell novel novel drug combination novel strategies novel therapeutic intervention pembrolizumab pre-clinical preclinical study predicting response predictive marker programmed cell death ligand 1 programs response response biomarker side effect skin squamous cell carcinoma targeted treatment treatment response tumor microenvironment tumor progression tumorigenic

项目摘要

Project Summary – Overall This Wistar/UPenn Skin SPORE represents a highly successful and longstanding collaboration. Immune checkpoint inhibition has revolutionized melanoma therapy to the point where every high-risk melanoma patient will be treated at some point with these agents. However, many major questions remain on how best to use these immune therapeutics. Project 1 will address the unmet need to find an effective biomarker to select patients for single agent versus combination immunotherapy. Many patients start treatment with ipilimumab and nivolumab, when they may have responded to anti-PD-1 antibody (Ab) alone, exposing these patients unnecessarily to the toxicity of combination checkpoint inhibition. Project 1 builds on a fundamental discovery made through our Developmental Research Program (DRP) that exosomal PD-L1 is an immunosuppressive factor secreted by melanomas. We propose rigorous clinical utility studies designed to demonstrate this blood- based measurement as a highly sensitive and specific predictive biomarker for anti-PD-1 antibody (Ab)-based therapy. Project 2 will address a second unmet need for a safer and effective combination regimen that promises to be effective in anti-PD-1 Ab refractory patients. Based on extensive preclinical data and a new molecular target in the autophagy pathway, we have developed a clinical trial of combined anti-PD1 Ab and autophagy inhibition, a new strategy for reprogramming tumor-associated macrophages to enhance the efficacy of T cell killing. Project 3 fills a major gap in the treatment of early disease by conducting a clinical trial with anti-PD1 Ab in Stage IIB/C melanoma patients. Besides in-depth characterization of the immune response, the Project’s preclinical studies will lead to new strategies for enhancing the immune stimulatory capacity of dendritic cells in the tumor microenvironment. These three highly translational Projects are supported by longstanding Cores that have a proven track record of adapting to the rapidly changing needs of melanoma and non-melanoma skin cancer researchers. Each Project was chosen by the current SPORE leadership for its potential for significance, impact and innovation. Together, they have the potential to advance therapeutically exploitable biological insights into new, clinically important therapies of patients with melanoma. Funding from the SPORE has provided us with important advantages, including a mature, collective, translational mindset, an efficiently functioning tumor bank, and a highly evolved framework of collaboration between The Wistar Institute and UPenn. The SPORE has allowed us to bolster horizontal and vertical collaborations with academic and industry partners throughout the world. The Career Enhancement Program and DRP have enabled transition to new leadership, have formed the three Projects proposed, and have allowed our research to reach into other cancers of the skin including SCC, CTCL and Merkel Cell carcinoma. These programs will continue to be supported robustly by strong institutional support from both Wistar and UPenn. Funding of this SPORE will bring new advances from the bench to the bedside and fulfill our overall mission of improving survival for skin cancer patients.

项目摘要-整体