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.

摘要： 转移性黑色素瘤是美国增长最快的肿瘤类型之一， 退伍军人癌症，也是治疗最具挑战性的恶性肿瘤之一。目前 靶向检查点抑制剂如CTLA-4和/或PD-1的免疫疗法可以增强T细胞 细胞对肿瘤的反应，这些抑制剂已经显示出巨大的成功，因此已经转移到 大多数转移性黑色素瘤患者的一线标准治疗。伊匹单抗（靶向CTLA-4） 与nivolumab（靶向PD-1）联合使用，在黑色素瘤患者中产生了59%的应答率。 突变负荷增加的黑色素瘤患者和NF 1突变的黑色素瘤患者对以下治疗的反应更好： 抗PD 1或抗PDL 1治疗。然而，副作用往往是广泛的，产生严重的不良反应， 抗CTLA 4和抗PD 1联合治疗可使>60%的患者发生包括心肌炎在内的不良事件。 显然，需要改进目前的治疗方法，以提高转移性黑色素瘤的生存率。 患者大约40%的黑色素瘤肿瘤具有CDKN 2A的突变或缺失。之一 由CDKN 2A编码的基因INK 4a对于抑制细胞周期激酶CDK 4/6是重要的。这 导致对细胞周期的限制丧失和黑素瘤肿瘤细胞的增殖增强。我们 已经表明，细胞周期激酶CDK 4/6的抑制剂可以减缓一些细胞的生长， 黑色素瘤肿瘤，还增强T细胞募集到肿瘤中。此外，约80% 的黑色素瘤患者在RAS/RAF/MEK/MAPK通路中存在激活突变（30%， NRAS突变和51% BRAF突变）。另外23%的人有改变， PI 3 K通路的激活。最近，rigosertib（RGS），一种非ATP竞争性多激酶 抑制剂，已显示抑制RAS/RAF/MEK和PI 3 K信号传导途径，其也是 对黑色素瘤的生长至关重要我们建议在这里确定结合的有效性 CDK 4/6抑制剂与RGS相比，抗PD 1治疗是标准治疗。我们 假设靶向多种激酶RGS将有效治疗RAS突变 黑色素瘤与CDK 4/6抑制剂的组合。我们还建议， 当添加检查点抑制剂如抗PD 1或CD 137活化抗体时， RGS和CDK 4/6 i联合治疗方案。在这项研究补助金中，我们将检查 CDK 4/6抑制剂联合RGS抑制免疫活性小鼠黑色素瘤生长 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黑色素瘤的WT）。 BRAF）。我们还将研究CDK 4/6抑制与RGS联合对免疫系统的影响。 对肿瘤的反应，并表征RGS与抗PD 1或其他抗PD 1抗体组合的有效性。 检查点抑制剂，或在免疫活性小鼠模型中添加抗CD 137治疗 黑色素瘤最后，我们将评估CDK 4/6抑制剂和RGS联合治疗的有效性， 使用人源化的抗PD 1或抗CD 137治疗黑素瘤患者来源的异种移植物 小鼠模型。这项研究将为治疗我们的糖尿病提供新的和改进的治疗选择。 患有转移性黑色素瘤的退伍军人。