Investigating concurrent Ras-pathway inhibition to optimize response to anti-PD-1 therapy in NRAS-mutant melanoma

研究并发 Ras 通路抑制以优化 NRAS 突变黑色素瘤抗 PD-1 治疗的反应

基本信息

批准号：
10330996
负责人：
Caroline Nebhan
金额：
$ 5.82万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10330996
关键词：
Address Aftercare B-Lymphocytes BRAF gene Binding Biomedical Engineering Body Weight CD34 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene CXCL1 gene CXCL9 gene Cell Death Cell Line Cell membrane Cells Clinical Trials Coculture Techniques Collaborations Combination immunotherapy Data Dendritic Cells Diagnosis Disease Engraftment Event Exhibits Frequencies Goals Growth Hematocrit procedure Hematologic Neoplasms Hematopoietic Human Immune checkpoint inhibitor Immunosuppression Immunotherapy Implant In Vitro Inflammatory Interferon Type II Interleukin-10 Interleukin-4 Laboratories Leukocytes Lymphocyte MEKs Measurement Measures Mediating Melanoma Cell Metastatic Melanoma Modeling Monitor Mus Mutation Natural Killer Cells Oncogenes Organoids PTPRC gene Pathway interactions Patient-Focused Outcomes Patients Phosphorylation Progression-Free Survivals Proteins RANTES Ras/Raf Research Resistance Sampling Signaling Molecule Skin Cancer Sulfones Survival Rate System T-Cell Activation TNF gene Testing Therapeutic Toxic effect Triplet Multiple Birth Tumor Immunity Tumor Markers Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells United States Work Xenograft Model Xenograft procedure anti-CTLA4 anti-PD-1 anti-PD1 therapy base checkpoint therapy cohort cytokine density draining lymph node driver mutation effective therapy experimental study humanized mouse immune activation improved outcome in vivo in vivo evaluation inhibitor/antagonist macrophage melanoma mimetics mouse model mutant neoplastic cell new therapeutic target novel novel therapeutics patient derived xenograft model preclinical study prevent programmed cell death ligand 1 programmed cell death protein 1 reconstitution response small molecule subcutaneous targeted agent targeted treatment treatment arm treatment effect treatment group treatment optimization treatment response treatment strategy tumor tumor growth tumor microenvironment

项目摘要

Project Summary/Abstract Melanoma is the most deadly form of skin cancer in the United States, with approximately 100,000 new cases diagnosed annually. Patients diagnosed with metastatic melanoma have previously suffered an abysmal 5-year survival rate, but a novel class of therapeutics termed immune checkpoint inhibitors (ICI) have changed the landscape of melanoma treatment. ICI therapy is effective in up to 50% of metastatic melanoma patients regardless of driver mutation, but work is needed to improve outcomes for patients. One such strategy is to combine targeted therapies, such as those used in BRAF-mutant melanoma, with ICI therapy. However, this strategy is limited by significant toxicity in BRAF-mutant patients and is ineffective in the 20% of patients whose tumors harbor NRAS driver mutations. Preliminary results suggest that rigosertib, a novel Ras-pathway inhibitor currently in clinical trials in hematologic malignancy, may enhance anti-tumor immunity. Our preliminary data show that treatment of melanoma tumors in mice with rigosertib induces an inflammatory tumor microenvironment, with enriched total and CD8+ dendritic cells and CD45-MHCII+ cells, elevated levels of both CD4+ and CD8+ T cells, B cells and NK cells, but decreased levels of PD-1+ CD4+ T cells and tumor-infiltrating macrophages. Rigosertib-treated melanoma tumors exhibit increased frequency and density of CD4+ and CD8+ T cells but very low levels of T cell activation in the tumor microenvironment. However, CD8+ T cells are strongly activated in the tumor-draining lymph nodes of rigosertib-treated tumors compared to activation under vehicle treatment, suggesting a potent immunosuppressive effect mediated by tumor microenvironment. These preliminary data provide a strong therapeutic basis for the use of immune checkpoint inhibitors (e.g., anti-PD-1) in combination with rigosertib to enhance anti-tumor immunity and optimize the treatment of melanoma. This hypothesis will be addressed by: 1) developing a microbioreactor system for the co-culture of human NRAS-mutant melanoma organoids with patient- matched leukocytes to evaluate the treatment response of NRAS-mutant melanoma cells to the combination of rigosertib plus α-PD-1 therapy as compared to α-PD1 alone, and 2) generating humanized patient-derived xenograft mouse models to determine the treatment response of NRAS- mutant melanoma cells to the combination of rigosertib plus α-PD-1 therapy as compared to either therapy alone. These studies will evaluate a promising novel treatment strategy with highly translational relevance to melanoma patients while also establishing critical models for further preclinical studies of immunotherapy.

项目摘要/摘要黑色素瘤是美国最致命的皮肤癌形式，约有100,000个新的每年诊断出病例。诊断为转移性黑色素瘤的患者以前患有糟糕的5年生存率，但一种新型理论称为免疫化学检查点抑制剂（ICI）改变了黑色素瘤治疗的景观。 ICI疗法可有效多达50％转移性黑色素瘤患者不论驱动突变如何，但需要工作以改善预后适用于患者。一种这样的策略是结合靶向疗法，例如在BRAF突变中使用的疗法黑色素瘤，ICI疗法。但是，该策略受到BRAF突变的毒性的限制患者且在20％的肿瘤具有NRAS驱动器突变的患者中无效。初步结果表明，Riposertib是一种新型的RAS-Pathway抑制剂，目前正在临床试验中血液系统恶性肿瘤可能会增强抗肿瘤免疫力。我们的初步数据表明治疗 Riposertib小鼠中黑色素瘤的肿瘤可诱导炎症性肿瘤微环境，并具有富集的总和CD8+树突状细胞以及CD45-MHCII+细胞，CD4+和CD8+的水平升高 T细胞，B细胞和NK细胞，但提高了PD-1+ CD4+ T细胞的水平和肿瘤浸润巨噬细胞。 Rigosertib处理的黑色素瘤肿瘤暴露于CD4+的频率和密度增加和CD8+ T细胞，但在肿瘤微环境中的T细胞激活水平非常低。但是，CD8+ 与Riposertib处理的肿瘤的肿瘤淋巴结中，T细胞强烈激活在车辆处理下激活，表明肿瘤介导的潜在免疫抑制作用微环境。这些初步数据为使用免疫提供了强大的理论基础检查点抑制剂（例如抗PD-1）与Riposertib结合使用，以增强抗肿瘤免疫力并优化黑色素瘤的治疗。该假设将通过：1）开发用于人类NRAS-突变的黑色素瘤类器官培养的微生物反应器系统与患者匹配的白细胞来评估NRAS-突变剂黑色素瘤细胞对与单独的α-PD1相比，Rigosertib加α-PD-1治疗的组合，2）产生人源化患者衍生的异种移植小鼠模型，以确定NRAS-的治疗反应与任何一个仅治疗。这些研究将通过高度翻译来评估有望的新颖治疗策略与黑色素瘤患者相关，同时还建立了关键模型，以进一步研究免疫疗法。