Combining Immune Therapy with Targeted Therapies to Improve Melanoma Survival

摘要：中国 转移性黑色素瘤是美国生长最快的肿瘤类型之一，位居前五位 癌症是退伍军人中的一种，也是最具挑战性的恶性肿瘤之一。目前 针对检查点抑制物如CTLA-4和/或PD-1的免疫疗法可以增强T细胞 细胞对肿瘤的反应和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护理。Ipilimumab(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%的有效率。 突变负荷增加的黑色素瘤患者和携带NF1突变的患者对 抗PD1或抗PDL1治疗。然而，副作用往往是广泛的，产生严重的不良反应。 联合抗CTLA4和抗PD1治疗的患者中有60%的患者发生心肌炎。 显然，需要改进目前的治疗方法来提高转移性黑色素瘤的存活率。 病人。约40%的黑色素瘤存在CDKN2A基因突变或缺失。其中一个 由CDKN2a、INK4a编码的基因对抑制细胞周期蛋白激酶CDK4/6起重要作用。 结果失去了对细胞周期的限制，促进了黑色素瘤细胞的增殖。我们 已经表明，细胞周期激酶的抑制剂CDK4/6都可以减缓一些 黑色素瘤还能增强T细胞在肿瘤中的募集。此外，大约80% 的黑色素瘤患者存在RAS/RAF/MEK/MAPK途径的激活突变(30%) NRAS突变和BRAF突变占51%)。另有23%的人进行了更改，导致 激活PI3K通路。新近发现的Rigosertib(RGS)，一种非三磷酸腺苷竞争性多激酶 抑制剂，已被证明抑制RAS/RAF/MEK和PI3K信号通路，这些信号通路也是 对黑色素瘤的生长至关重要。我们建议在这里确定组合的有效性 CDK4/6抑制剂联合RGS与抗PD1治疗的比较，后者是标准护理。我们 假设靶向多个激酶的RGS对治疗RAS突变有效 黑色素瘤联合CDK4/6抑制剂。我们还建议，更大的回应将是 当加入检查点抑制物，如抗PD1或激活CD137抗体时发生 RGS与CDK4/6I联合治疗方案。在这项研究拨款中，我们将考察 CDK4/6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、BRAF突变和B16黑色素瘤(WT用于NRAS和 BRAF)。我们还将研究CDK4/6抑制和RGS对免疫的影响 对肿瘤的反应和RGS与抗PD1或其他药物联合的有效性 Check Point抑制剂或加用抗CD137治疗免疫功能正常的小鼠模型 黑色素瘤。最后，我们将评估CDK4/6抑制剂和RGS联合应用的有效性。 人源化抗PD1或抗CD137治疗黑色素瘤患者移植瘤 老鼠模型。这项研究应该会带来新的和改进的治疗方案来治疗我们的 患有转移性黑色素瘤的退伍军人。

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.