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.

抽象的：转移性黑色素瘤是美国增长最快的肿瘤类型之一，也是排名前 5 位的肿瘤类型之一退伍军人中的癌症，也是目前最具挑战性的恶性肿瘤之一。针对检查点抑制剂（例如 CTLA-4 和/或 PD-1）的免疫疗法可以增强 T 细胞对肿瘤的反应，这些抑制剂已显示出巨大的成功，因此已转向大多数转移性黑色素瘤患者的一线标准治疗（针对 CTLA-4）。与纳武单抗（针对 PD-1）联合治疗黑色素瘤患者的缓解率为 59%。突变负荷增加的黑色素瘤患者以及具有 NF1 突变的患者对然而，抗PD1或抗PDL1疗法的副作用往往很广泛，产生严重的不良反应。抗 CTLA4 和抗 PD1 联合治疗导致超过 60% 的患者发生事件，包括心肌炎。显然，需要改进当前的治疗方法以提高转移性黑色素瘤的生存率大约 40% 的黑色素瘤患者存在 CDKN2A 突变或缺失。 CDKN2A、INK4a 编码的基因对于抑制细胞周期激酶 CDK4/6 很重要。导致细胞周期限制的丧失和黑色素瘤细胞增殖的增强。研究表明，细胞周期激酶 CDK4/6 的抑制剂可以减缓某些细胞的生长。此外，大约 80% 的黑色素瘤也会增强 T 细胞的募集。的黑色素瘤患者在 RAS/RAF/MEK/MAPK 通路中存在激活突变（30% NRAS 突变，51% 发生 BRAF 突变），另外 23% 发生改变。最近，rigosertib (RGS) 是一种非 ATP 竞争性多激酶。抑制剂，已被证明可以抑制 RAS/RAF/MEK 和 PI3K 信号通路，这些信号通路也被我们在此建议确定组合的有效性。 CDK4/6 抑制剂联合 RGS 与标准治疗的抗 PD1 疗法相比。坚持认为针对多种激酶的 RGS 将有效治疗 RAS 突变体我们还建议，与 CDK4/6 抑制剂联合治疗黑色素瘤，效果会更好。当添加检查点抑制剂（例如抗 PD1 或 CD137 激活抗体）时会发生这种情况在这项研究资助中，我们将检查 RGS 和 CDK4/6i 联合治疗方案的能力。 CDK4/6联合抑制剂与RGS抑制免疫活性小鼠黑色素瘤的生长黑色素瘤模型，包括 NRAS 突变体、BRAF 突变体和 B16 黑色素瘤（NRAS 和 B16 的 WT BRAF）我们还将研究 CDK4/6 抑制与 RGS 联合对免疫的影响。对肿瘤的反应并表征 RGS 与抗 PD1 或其他药物联合使用的有效性检查点抑制剂，或在免疫能力强的小鼠模型中添加抗 CD137 治疗最后，我们将评估 CDK4/6 抑制剂和 RGS 联合治疗的有效性。抗PD1或抗CD137用于使用人源化治疗黑色素瘤患者来源的异种移植物这项研究应该为治疗我们的疾病带来新的和改进的治疗选择。患有转移性黑色素瘤的退伍军人。