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

• 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
• 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

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，是前5个 退伍军人中的癌症，也是治疗的最挑战的挑战之一。现在 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 细胞对肿瘤的反应和这些抑制剂已显示出巨大的成功，因此已移至 大多数转移性黑色素瘤患者的一线护理标准。 ipilimumab（靶向CTLA-4） 黑色素瘤患者的Nivolumab（靶向PD-1）结合得出了59％的缓解率。 突变负荷增加的黑色素瘤患者，并且患有NF1突变的患者对 抗PD1或抗PDL1治疗。但是，副作用通常是广泛的，会产生严重的逆境 > 60％的患者中，包括抗CTLA4和抗PD1治疗的患者中的事件。 显然，需要对当前治疗的改进来增强转移性黑色素瘤的存活率 患者。大约40％的黑色素瘤肿瘤具有CDKN2A的突变或丧失。中的一个 由CDKN2A编码的基因Ink4a对于抑制细胞周期激酶CDK4/6很重要。这 导致细胞周期限制的损失和黑色素瘤细胞增殖的增强。我们 已经表明，细胞周期激酶CDK4/6的抑制剂都可以减慢某些的生长 黑色素瘤肿瘤，还增强了T细胞募集到肿瘤中。而且，大约80％ 黑色素瘤患者在RAS/RAF/MEK/MAPK途径中具有激活突变（30％ NRA中的突变，为BRAF突变为51％。另有23％的变化导致 PI3K途径的激活。近期Rigosertib（RGS），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信号传导途径 对于黑色素瘤肿瘤生长至关重要。我们在这里建议确定合并的有效性 与抗PD1治疗相比，具有RGS的CDK4/6抑制剂是护理标准。我们 假设靶向多种激酶的RGS将有效治疗RAS突变体 黑色素瘤与CDK4/6抑制剂结合使用。我们还提出，更大的回应将会 将检查点抑制剂（例如抗PD1或与CD137激活抗体）添加到 RGS和CDK4/6i联合治疗方案。在这项研究赠款中，我们将研究 CDK4/6抑制剂与RGS结合以抑制免疫能力小鼠中黑色素瘤的生长 黑色素瘤模型，包括NRAS突变体，BRAF突变体和B16黑色素瘤（NRA和NRA和 BRAF）。我们还将检查CDK4/6抑制与RGS对免疫的影响 对肿瘤的反应并表征将RG与抗PD1或其他组合的有效性 检查点抑制剂，或在免疫能力小鼠模型中添加抗CD137治疗 黑色素瘤。最后，我们将评估将CDK4/6抑制剂和RG与 抗PD1或抗CD137用于使用人源化治疗黑色素瘤患者衍生的Xenographics 鼠标模型。这项研究应导致新的和改进的治疗方法来治疗我们 具有转移性黑色素瘤的退伍军人。