权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of Bim and soluble B7-H1 in monitoring T cell responses to anti-PD-1 therapy in melanoma

Bim 和可溶性 B7-H1 在监测黑色素瘤 T 细胞对抗 PD-1 治疗反应中的作用

基本信息

批准号：
9127910
负责人：
Haidong Dong
金额：
$ 16.96万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-17 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9127910
关键词：
Affect Antibodies Apoptosis Apoptotic Binding Biological Markers Blocking Antibodies Blood Circulation CD8B1 gene Cessation of life Clinical Clinical Trials Cytotoxic T-Lymphocytes Data Disease Disease Progression Ensure FDA approved Hand Health Immune Immunity Immunosuppressive Agents Immunotherapeutic agent Immunotherapy In complete remission Institution Lead Ligands Malignant Neoplasms Measurement Metastatic Melanoma Modeling Monitor Monoclonal Antibodies Outcome PDCD1LG1 gene Pathway interactions Patients Proteins Public Health Research Resistance Role Serum Signal Transduction Signaling Molecule Site T cell response T-Lymphocyte Testing Therapeutic Effect Toxic effect Treatment outcome Tumor Burden Up-Regulation Work base biomarker development biomarker discovery cancer cell cancer therapy clinical investigation combinatorial drug efficacy exhaust experience health care economics in vivo innovation melanoma neutralizing antibody new therapeutic target novel novel marker open label patient population patient subsets peripheral blood personalized approach personalized strategies predictive marker programs receptor resistance mechanism responders and non-responders response response biomarker therapeutic target therapy outcome therapy resistant treatment response tumor

项目摘要

DESCRIPTION (provided by applicant): Given the variability in response to the novel immunotherapeutic agents and the desire to extend their long- term benefits to more patients, there is an increased need for the development of biomarkers that can predict treatment outcomes, thereby ensure that these expensive new treatments, which may have significant toxicities, are offered to the patients who are more likely to benefit. The FDA approved anti-PD1 agent (pembrolizumab/MK3475) typifies this phenomenon of dramatic therapeutic responses in a subset of patients who cannot be pre-identified, necessitating broad treatment application in an unselected patient population. The objective in this application is to evaluate and validate Bim (a PD-1 downstream signaling molecule) levels in tumor-reactive PD-1+ T cells, as well as soluble B7-H1(PD-L1), as monitoring or predictive biomarkers for response to anti-PD-1 therapy in patients with metastatic melanoma (MM), an excellent model, as PD-1/PD-L1 pathway is an increasingly exploited therapeutic target in this disease and a variety of other cancers, with extremely promising results in clinical trials. Our central hypothesis is that Bim levels in tumor-reactive CD11a high D-1+CD8+ peripheral blood T cells can objectively monitor responses to anti-PD-1 therapy and that excessive release of soluble B7-H1 by the tumor leads to Bim upregulation and treatment resistance in melanoma. This hypothesis will be tested in MM patients undergoing treatment with an anti-PD-1 monoclonal antibody (pembrolizumab) at our Institution. Guided by strong preliminary data, we propose two Specific Aims to test our central hypothesis: 1) Establish the role of Bim for monitoring disease status during anti-PD-1 therapy; and 2) Identify the mechanisms of resistance to anti-PD-1 blockade. In aim 1, an already proven PD-1 downstream signaling molecule Bim (the pro-apoptotic BH3-only protein), which has been established as a feasible marker for the status of PD-1 engagement in the applicants' hands, will be utilized to monitor and predict the T cell responses to anti-PD-1 therapy, as well as identify patients who may achieve late clinical benefit despite radiologic pseudoprogression. Under aim 2, we will explore that soluble B7-H1 (PD-L1) could influence the sensitivity to anti-PD-1 therapy and be a new therapeutic target of dual blocker therapy (anti-PD-1 and anti-PD-L). Our approach is innovative because it utilizes novel markers to assess the reversibility of exhausted anti-tumor PD-1+ T cells and the efficiency of anti-PD-1 blockade, which would directly influence the therapeutic outcome with anti-PD-1 therapy. Our proposed research is significant, because our results could help identify patients with melanoma (and possibly other malignancies) who are most likely to benefit from anti- PD-1 therapy, therefore increasing drug efficacy and decreasing toxicity through a more personalized approach to cancer treatment.