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Combining Immune Therapy with Targeted Therapies to Improve Melanoma Survival

免疫治疗与靶向治疗相结合以提高黑色素瘤的生存率

基本信息

批准号：
10265337
负责人：
Ann Richmond
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-10-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265337
关键词：
American Society of Clinical Oncology Antibodies BRAF gene Binding CDK4 gene CDKN2A gene CTLA4 gene Cell Cycle Chromosome 7 Chromosome 8 Clinical Trials Colorectal Cancer Cytogenetics Disease Disease regression Dysmyelopoietic Syndromes Effectiveness Exhibits Gene Mutation Gene Targeting Genes Grant Growth Human Immune response Immunocompetent Immunotherapy Lactate Dehydrogenase Lead Leukocytes Life Low-Density Lipoproteins MAP Kinase Gene MEKs Malignant Neoplasms Malignant neoplasm of lung Metastatic Melanoma Modeling Monosomy Mutate Mutation Myocarditis NF1 mutation Neoplasm Metastasis Nivolumab PLK1 gene Pathway interactions Patients Phosphotransferases Progression-Free Survivals Proteins Proto-Oncogene Proteins c-akt Ras/Raf Reporting Research Research Project Grants Resistance Resistance development Safety Serious Adverse Event Signal Pathway Signal Transduction Site Stable Disease T cell response T-Lymphocyte Therapeutic Time Transgenic Model Trisomy Veterans Xenograft procedure anti-CTLA4 anti-PD-1 anti-PD-L1 therapy anti-PD1 therapy base cancer cell effectiveness evaluation fighting humanized mouse improved inhibitor/antagonist ipilimumab kinase inhibitor meetings melanoma mouse model mutant neoplastic cell pancreatic cancer model patient derived xenograft model phase 3 study programmed cell death protein 1 recruit response side effect small molecule inhibitor standard of care success targeted treatment tumor tumor growth

项目摘要

ABSTRACT: Metastatic melanoma is one of the fastest growing tumor types in the US, one of the top 5 cancers among Veterans, and is also one of the most challenging malignancies to treat. Currently immune therapies targeting the check-point inhibitors such as CTLA-4 and/or PD-1 can enhance the T cell response to tumor an these inhibitors have shown great success and as a result have moved to first line standard of care for most metastatic melanoma patients. Ipilimumab (targeting CTLA-4) combined with nivolumab (targeting PD-1) has yielded a 59% response rate in melanoma patients. Melanoma patients with an increased mutational load, and those with NF1 mutation, respond better to anti-PD1 or anti-PDL1 therapy. However, side effects are often extensive, producing severe adverse events in >60% of patients including myocarditis for combined anti-CTLA4 and anti-PD1 therapy. Clearly, refinements of current treatments are needed to enhance survival of metastatic melanoma patients. Approximately 40% of melanoma tumors have mutation or loss of CDKN2A. One of the genes encoded by CDKN2A, INK4a is important for inhibiting the cell cycle kinases, CDK4/6. This results in loss of restrictions on cell cycle and enhanced proliferation of melanoma tumor cells. We have shown that inhibitors of the cell cycle kinases, CDK4/6, can both slow the growth of some melanoma tumors and also enhance T cell recruitment into the tumors. Moreover, approximately 80% of melanoma patients have activating mutations in the RAS/RAF/MEK/MAPK pathway (30% with mutation in NRAS and 51% with mutation of BRAF). Another 23% have alterations resulting in activation of the PI3K pathway. Recently rigosertib (RGS), a non-ATP competitive multi-kinase inhibitor, has been shown to inhibit the RAS/RAF/MEK and PI3K signaling pathways which are also crucial for melanoma tumor growth. We propose here to determine the effectiveness of combining CDK4/6 inhibitors with RGS in comparison to anti-PD1 therapy which is standard of care. We hypothesize that RGS, which targets multiple kinases, will be effective for treating RAS mutant melanoma in combination with CDK4/6 inhibitors. We also propose that an even greater response will occur when check point inhibitors such as anti- PD1 or with activating antibody to CD137 are added to the RGS and CDK4/6i combined therapy regime. In this research grant we will examine the ability of CDK4/6 inhibitor combined with RGS to inhibit the growth of melanoma in immune competent mouse models of melanoma, including NRAS mutant, BRAF mutant, and B16 melanoma (WT for NRAS and BRAF). We will also examine the effects of CDK4/6 inhibition combined with RGS on the immune response to the tumor and characterize the effectiveness of combining RGS with anti-PD1 or other check point inhibitors, or with addition of anti-CD137 treatment in immune competent mouse models of melanoma. Finally, we will evaluate the effectiveness of combining CDK4/6 inhibitor and RGS with anti-PD1 or anti-CD137 for treatment of melanoma patient derived xenografts using humanized mouse models. This study should lead to new and improved therapeutic options for treating our Veterans with metastatic melanoma.

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