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: 10369756
• 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 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369756
• 关键词: Address; Agonist; Antibodies; BRAF gene; Biological Assay; CD8-Positive T-Lymphocytes; CTLA4 gene; Cell Death; Cells; Clinical Trials; Coculture Techniques; Data; Dendritic Cells; Development; Disease; Effectiveness; Environment; Event; Excision; Exhibits; Flow Cytometry; Frequencies; Growth; Human; IL8RA gene; IL8RB gene; Immune; Immune checkpoint inhibitor; Immunization; Immunocompetent; Immunotherapeutic agent; Immunotherapy; In complete remission; Lactate Dehydrogenase; MEKs; Malignant Neoplasms; Mediating; Melanoma Cell; Metastatic Melanoma; Mutation; Myeloid-derived suppressor cells; Myocarditis; NF1 mutation; Natural Killer Cells; Nivolumab; Organoids; PD-1/PD-L1; Patients; Persons; Pre-Clinical Model; Production; Ras/Raf; Resistance; Resistance development; Role; Stable Disease; Survival Rate; System; TNFRSF5 gene; Therapeutic; Treatment-related toxicity; Tumor Immunity; Tumor-associated macrophages; Veterans; antagonist; anti-CTLA4; anti-PD-1; anti-PD-L1; anti-PD1 therapy; anti-tumor immune response; base; checkpoint therapy; cytokine; draining lymph node; experience; high risk; immune checkpoint blockade; immunogenic; immunogenic cell death; improved; improved outcome; inhibitor; insight; ipilimumab; knock-down; melanoma; mimetics; mouse model; mutant; neoplastic cell; novel therapeutic intervention; pembrolizumab; prognostic; programmed cell death ligand 1; recruit; response; single-cell RNA sequencing; small molecule inhibitor; standard of care; survival outcome; targeted treatment; therapy resistant; transcriptome; treatment response; tumor; tumor growth; tumor-immune system interactions

Metastatic melanoma is one of the fastest growing tumor types in the US and our Veterans are at higher risk for developing melanoma. Recent therapeutic advances in immunotherapy utilizing immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced/metastatic melanoma. Antibodies targeting PD-1/PD-L1 (nivolumab, pembrolizumab, atezolizumab) and CTLA-4 (ipilimumab) evoke powerful anti-melanoma immune responses1,2,3. For metastatic disease, treatment with ipilimumab combined with nivolumab or nivolumab alone has demonstrated 5-year overall survival (OS) rates of 52% and 44%, respectively, with many patients experiencing exceptional response. Despite improvement in survival outcomes with ICIs, the majority of patients either fail to respond or develop resistance to ICIs. Novel therapeutic strategies are needed to improve outcomes for melanoma patients treated with ICI and to address acquired resistance. Development of new therapeutic approaches for melanoma patients who exhibit primary or acquired resistance to ICI therapy is the focus of our proposal. Our preliminary data from preclinical models indicate that combining the Ras mimetic, rigosertib (RGS) with ICI significantly reduces melanoma tumor growth, even in tumors that are poorly responsive to ICIs. RGS treatment results in a tumor immune microenvironment (TIME) enriched in CD8+T cells, dendritic cells (DCs) and natural killer cells, but does not reduce intratumoral myeloid-derived suppressor cells (MDSCs). RGS also increases CD40 expression on the melanoma tumor cells to facilitate immunogenic tumor cell death. In the absence of CD40 expression by tumor cells, or without CD8+T cells in the TIME, RGS’s anti-tumor activity is lost. We hypothesize that RGS-induced expression of CD40 in melanoma cells is a key component of RGS-enhanced anti-tumor immunity and that addition of a CD40 agonist to the RGS +ICI will enhance CD40- mediated immunogenic cell death. We also propose that addition of a CXCR1/2 antagonist to the RGS+ICI therapy will block MDSC recruitment to tumor, allowing prolonged CD8+T cell anti-tumor activity. Either of these approaches would further activate the anti-tumor immune response to induce tumor regression. We will pursue three specific aims to address this hypothesis. Aim 1: To determine the mechanism by which RGS induces expression of CD40 on tumor cells and to characterize the role of tumor cell CD40 in restoring response to ICI in immunocompetent mouse models of melanoma. Aim 2. To evaluate whether addition of a CD40 agonist antibody will enhance sensitivity of melanoma tumors to RGS + ICI and define mechanisms of response using mouse models and human organoid co-culture systems. Tumoral, immune, and transcriptome changes will be evaluated through multicolor flow cytometry and single cell(sc) RNAseq analysis to provide mechanistic insight on how this combined therapy modulates response to therapy. Aim 3: To determine whether RGS combined with a CXCR1/2 antagonist, can re-sensitize melanoma tumors to ICI therapy using similar approaches as for Aim 2. Significance: These studies will result in new therapeutic approaches to improve treatment of metastatic melanoma in our Veterans by enhancing response to ICI therapies or re-sensitizing ICI-resistant tumors to treatment with ICI.

转移性黑色素瘤是美国增长最快的肿瘤类型之一，我们的退伍军人面临更高的风险 发展为黑色素瘤。利用免疫检查点抑制剂（ICIs）进行免疫疗法的最新治疗进展 彻底改变了晚期/转移性黑色素瘤的治疗。靶向 PD-1/PD-L1 的抗体（纳武单抗、 pembrolizumab、atezolizumab）和 CTLA-4（ipilimumab）可引起强大的抗黑色素瘤免疫反应1,2,3。 对于转移性疾病，伊匹单抗联合纳武单抗或单独纳武单抗治疗已经证明 5 年总生存 (OS) 率分别为 52% 和 44%，许多患者经历了特殊的情况 回复。尽管 ICI 改善了生存结果，但大多数患者要么没有反应，要么 产生对 ICI 的耐药性。需要新的治疗策略来改善黑色素瘤患者的预后 用 ICI 治疗并解决获得性耐药问题。开发新的治疗方法 对 ICI 治疗表现出原发性或获得性耐药的黑色素瘤患者是我们建议的重点。我们的 临床前模型的初步数据表明，Ras 模拟物 rigosertib (RGS) 与 ICI 相结合 显着减少黑色素瘤的生长，即使是对 ICI 反应不佳的肿瘤。 RGS 治疗导致肿瘤免疫微环境 (TIME) 富含 CD8+T 细胞、树突状细胞 (DC) 和自然杀伤细胞，但不会减少瘤内骨髓源性抑制细胞 (MDSC)。 RGS 还增加黑色素瘤细胞上 CD40 的表达，以促进免疫原性肿瘤细胞死亡。在 肿瘤细胞不表达 CD40，或 TIME 内不表达 CD8+T 细胞，RGS 的抗肿瘤活性 丢失了。我们假设 RGS 诱导的黑色素瘤细胞中 CD40 的表达是 RGS 增强抗肿瘤免疫力，并且在 RGS +ICI 中添加 CD40 激动剂将增强 CD40- 介导的免疫原性细胞死亡。我们还建议在 RGS+ICI 中添加 CXCR1/2 拮抗剂 治疗将阻止 MDSC 募集至肿瘤，从而延长 CD8+T 细胞的抗肿瘤活性。任一 这些方法将进一步激活抗肿瘤免疫反应，诱导肿瘤消退。 我们将追求三个具体目标来解决这一假设。目标 1：确定机制 RGS 诱导肿瘤细胞上 CD40 的表达并表征肿瘤细胞 CD40 在恢复中的作用 免疫功能正常的黑色素瘤小鼠模型对 ICI 的反应。目标 2. 评估是否添加 CD40激动剂抗体将增强黑色素瘤肿瘤对RGS + ICI的敏感性并确定机制 使用小鼠模型和人类类器官共培养系统进行反应。肿瘤、免疫和 转录组变化将通过多色流式细胞术和单细胞 (sc) RNAseq 进行评估 分析以提供有关这种联合疗法如何调节治疗反应的机制见解。目标 3： 确定 RGS 与 CXCR1/2 拮抗剂联合是否可以使黑色素瘤肿瘤对 ICI 重新敏感 使用与目标 2 类似的方法进行治疗。意义：这些研究将产生新的治疗方法 通过增强对 ICI 的反应来改善退伍军人转移性黑色素瘤治疗的方法 治疗或使 ICI 耐药肿瘤对 ICI 治疗重新敏感。