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：
10609814
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 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10609814
关键词：
Address Agonist Antibodies BRAF gene Biological Assay CD8-Positive T-Lymphocytes CTLA4 gene Cell Death Cells Clinical Trials Coculture Techniques Color Combined Modality Therapy Data Dendritic Cells Development Disease Environment Event Excision Exhibits Flow Cytometry Frequencies Growth Human IL8RA gene IL8RB gene Immune Immune checkpoint inhibitor Immune response Immunocompetent Immunologic Sensitization Immunotherapeutic agent Immunotherapy In complete remission Inflammatory 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 PIK3CG gene Patients Persons Pre-Clinical Model Production Ras/Raf Resistance Resistance development Role Serious Adverse Event Stable Disease Survival Rate System TNFRSF5 gene Therapeutic Treatment-related toxicity Tumor Immunity Tumor-associated macrophages Veterans Visualization antagonist anti-CTLA4 anti-PD-1 anti-PD-L1 therapy anti-PD1 therapy anti-tumor immune response checkpoint therapy cytokine draining lymph node effectiveness evaluation 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

项目摘要

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着更高的风险发育中的黑色素瘤。使用免疫检查点抑制剂（ICI）的免疫疗法的最新治疗进展已经彻底改变了晚期/转移性黑色素瘤的治疗。靶向PD-1/PD-L1的抗体（Nivolumab， Pembrolizumab，Atezolizumab）和CTLA-4（ipilimumab）唤起强大的抗黑素瘤免疫调查1,2,3。对于转移性疾病，ipilimumab与Nivolumab或Nivolumab合并的治疗已证明 5年的总生存率（OS）分别为52％和44％，许多患者出色回复。尽管ICIS的生存结果有所改善，但大多数患者无法做出反应或对ICIS的发展抵抗力。需要新的治疗策略来改善黑色素瘤患者的预后用ICI处理并解决获得的抗性。开发新的治疗方法暴露于原发性或获得ICI治疗的耐药性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，将Ras Mimetic，Rigosertib（RGS）与ICI结合即使在对ICI的反应不良的肿瘤中，也会显着降低黑色素瘤肿瘤的生长。 RGS 治疗导致富含CD8+T细胞，树突状细胞（DCS）的肿瘤免疫微环境（时间）和天然杀伤细胞，但不会减少肿瘤内髓样衍生的抑制细胞（MDSC）。 RGS 还增加了在黑色素瘤肿瘤细胞上的CD40表达，以促进免疫原性肿瘤细胞死亡。在 RGS的抗肿瘤活性在肿瘤细胞中不存在CD40表达，或者没有CD8+T细胞迷路了。我们假设RGS诱导的CD40在黑色素瘤细胞中的表达是 RGS增强的抗肿瘤免疫力以及在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募集到肿瘤，从而延长CD8+T细胞抗肿瘤活性。任何一个这些方法将进一步激活抗肿瘤免疫反应以诱导肿瘤消退。我们将追求三个特定的目标来解决这一假设。目标1：确定其机制 RGS影响CD40对肿瘤细胞的表达，并表征肿瘤细胞CD40的作用在黑色素瘤的免疫能力小鼠模型中对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的敏感性并定义机制使用小鼠模型和人类器官共培养系统的响应。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评估分析以提供有关这种联合治疗如何调节对治疗的反应的机理见解。目标3：为了确定RGS是否与CXCR1/2拮抗剂合并，可以将黑色素瘤重新敏感到ICI 使用与目标2相似的方法的治疗。意义：这些研究将导致新的疗法通过增强对ICI的反应来改善退伍军人中转移性黑色素瘤的治疗方法治疗或重新敏感性ICI肿瘤以用ICI治疗。