New Strategies for Treatment of NRAS Mutant Melanoma after Progression on Immune Checkpoint Inhibitors

免疫检查点抑制剂进展后治疗 NRAS 突变黑色素瘤的新策略

• 批准号: 10377505
• 负责人: Ann Richmond
• 金额: $ 37.27万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-19 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10377505
• 关键词: Achievement; Agonist; Apoptosis; BRAF gene; CD8-Positive T-Lymphocytes; CDK4 gene; CDKN2A gene; CTLA4 gene; CXC Chemokines; Cell Cycle Regulation; Cell Death; Cell Proliferation; Clinical Trials; Coculture Techniques; Combined Modality Therapy; Data; Disease; Disease Progression; Environment; Exhibits; Flow Cytometry; Future; Growth; Human; IL8RA gene; IL8RB gene; Immune; Immune checkpoint inhibitor; Immune response; Immunocompetent; Immunotherapy; Life; Link; MDM2 gene; MEKs; Malignant Neoplasms; Mediating; Metastatic Melanoma; Modeling; Mus; Mutation; Myeloid Cells; Myeloid-derived suppressor cells; Myocarditis; NF1 mutation; NRAS gene; Neoplasm Metastasis; Nivolumab; Organoids; PD-1/PD-L1; PTEN gene; Patients; Pharmaceutical Preparations; Phase; Phosphotransferases; Play; Process; Protein Array; Resistance; Resistance development; Role; Serious Adverse Event; Stable Disease; T-Lymphocyte; TP53 gene; Time; Translating; Treatment Efficacy; Tumor Angiogenesis; Tumor Immunity; Tumor-infiltrating immune cells; Ubiquitination; antagonist; anti-CTLA4; anti-PD-1; anti-PD-L1 therapy; anti-PD1 therapy; cell growth; checkpoint therapy; epigenetic silencing; experience; inhibitor; ipilimumab; melanocyte; melanoma; mouse model; mutant; neoplastic cell; patient derived xenograft model; recruit; response; senescence; side effect; single-cell RNA sequencing; standard of care; transcriptome; treatment response; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions; tumorigenesis

Treatment of metastatic melanoma with immune checkpoint inhibitors (ICI) has extended the life of many melanoma patients, but the vast majority of patient experience disease progression, prompting the need for alternate therapies. For ~50% of patients with BRAFmut tumors, treatment with BRAF and MEK inhibitors provide a good second-line treatment option. Unfortunately, there are few second-line options for the 25-30% of patients whose tumors harbor NRAS mutations. Since nearly 40% of all melanoma patients exhibit loss, mutation, or epigenetic silencing of the CDK4/6 regulator CDKN2A, we postulate that inhibition of CDK4/6 may induce response in NRASmut RBWT tumors with loss of CDKN2A. Because loss of CDKN2A also disrupts ARF, a suppressor of MDM2-mediated degradation of p53, it will be essential to also inhibit MDM2 to restore cell cycle control in p53WT melanoma. We have shown that NRASmut melanoma tumors with acquired resistance to ICI respond to co-treatment with a CDK4/6 inhibitor plus an MDM2, demonstrating both with reduced tumor growth and enhanced CD8+T cell recruitment into the tumor. These tumors contain a significant number of CXCR1,2 expressing myeloid-derived suppressor cells (MDSCs) that create an immune suppressive tumor microenvironment. Our preliminary data show that when CXCR2 is deleted in myeloid cells, MDSC recruitment to tumor is reduced and tumor growth is inhibited. Moreover, systemic delivery of a CXCR1,2 inhibitor reduced the growth of NRASmut melanoma in mice (p<0.02), and inducible deletion of CXCR2 in melanocytes blocks melanoma formation in the inducible BRAFV600E/PTEN-/- melanoma mouse model. These intriguing findings support prior studies indicating a role for CXCR2 inhibitors for treatment of melanoma. However, the mechanisms and generality of response to CXCR1,2 antagonism require further elucidation. Premise and Hypothesis: CXCR2 plays critical and pleotropic role in melanoma by promoting tumorigenesis and inducing an immunosuppressive tumor environment. Moreover, combined CDK4/6 and MDM2 inhibition significantly inhibits the growth of mouse and human NRASmut melanoma tumors. We hypothesize that co-inhibition of CXCR1,2, CDK4/6, and MDM2 in NRASmut melanoma with acquired resistance to ICI will inhibit tumor cell proliferation, induce tumor cell death, stimulate anti- tumor immunity, and potentially overcome the acquired resistance to ICI. We propose 3 specific aims. 1)To examine the ability of CDK4/6i plus MDM2i, combined with a CXCR1,2 antagonist treatment, or CXCR1,2 agonist alone, to enhance or restore ICI sensitivity for NRASmut melanoma tumors. 2) To determine the role of melanocyte-expressed CXCR2 in melanoma initiation. CXCR2 will be deleted coincident with induction of melanoma formation in mice and effects of this deletion on melanocyte apoptosis, senescence, differentiation and proliferation will be characterized. 3) To determine whether findings in mouse translate to human melanoma, changes in the tumor immune microenvironment (TIME) will be characterized over time in response to a CXCR1,2 antagonist (CXCR1,2i) with or without CDK4/6i+MDM2i followed by ICI therapy in humanized NRASmut patient-derived xenograft (PDX) models and human NRAS mut melanoma organoid co-cultures. These data will inform future clinical trials.

用免疫检查点抑制剂（ICI）治疗转移性黑色素瘤延长了许多黑色素瘤的寿命 患者，但绝大多数患者经历疾病进展，提示需要替代疗法。 对于约50%的BRAFMut肿瘤患者，BRAF和MEK抑制剂治疗提供了良好的二线治疗， 治疗选择不幸的是，对于25-30%的肿瘤患者来说，几乎没有二线治疗的选择。 NRAS突变。由于近40%的黑色素瘤患者表现出黑色素瘤基因的缺失、突变或表观遗传沉默， CDK 4/6调节因子CDKN 2A，我们推测抑制CDK 4/6可以诱导NRASmut RBWT肿瘤的反应， 失去CDKN 2A。由于CDKN 2A的缺失也破坏了ARF，ARF是MDM 2介导的细胞因子降解的抑制因子。 p53，也必须抑制MDM 2以恢复p53 WT黑素瘤中的细胞周期控制。我们已经证明 对ICI具有获得性耐药性的NRASmut黑色素瘤对CDK 4/6抑制剂加抗肿瘤药物的联合治疗有反应。 MDM 2，证明了肿瘤生长减少和CD 8 +T细胞募集到肿瘤中的增强。这些 肿瘤含有大量表达CXCR 1，2的髓源性抑制细胞（MDSC）， 免疫抑制肿瘤微环境。我们的初步数据显示，当骨髓中CXCR 2缺失时， 细胞，MDSC向肿瘤的募集减少，肿瘤生长受到抑制。此外，全身递送CXCR 1，2 抑制剂减少小鼠NRASmut黑素瘤的生长（p<0.02），并诱导黑素细胞中CXCR 2的缺失 在可诱导的BRAFV 600 E/PTEN-/-黑色素瘤小鼠模型中阻断黑色素瘤形成。这些有趣的发现 支持表明CXCR 2抑制剂治疗黑色素瘤的作用的先前研究。然而，机制 对CXCR 1，2拮抗作用的反应的一般性需要进一步阐明。假设和假设：CXCR 2 通过促进肿瘤发生和诱导免疫抑制性肿瘤，在黑色素瘤中起关键和多效性作用 环境此外，联合的CDK 4/6和MDM 2抑制显著抑制小鼠和人的生长。 NRASmut黑色素瘤。我们假设NRASmut中CXCR 1、2、CDK 4/6和MDM 2的共抑制作用可能与NRASmut中CXCR 1、2、CDK 4/6和MDM 2的表达有关。 黑色素瘤对ICI的获得性耐药可抑制肿瘤细胞增殖，诱导肿瘤细胞死亡，刺激抗- 肿瘤免疫，并有可能克服对ICI的获得性耐药性。我们提出三个具体目标。1）检查 CDK 4/6 i加MDM 2 i与CXCR 1，2拮抗剂治疗组合或单独CXCR 1，2激动剂， 增强或恢复NRASmut黑色素瘤的ICI敏感性。2)为了确定黑素细胞表达的 CXCR 2在黑色素瘤发生中的作用CXCR 2将与小鼠中黑色素瘤形成的诱导同时缺失， 将描述这种缺失对黑素细胞凋亡、衰老、分化和增殖的影响。 3)为了确定小鼠中的发现是否转化为人类黑色素瘤，肿瘤免疫功能的变化， 微环境（TIME）将随时间响应于CXCR 1，2拮抗剂（CXCR 1，2 i）而表征， 在人源化NRASmut患者来源的异种移植物（PDX）模型中， 人NRAS突变黑素瘤类器官共培养物。这些数据将为未来的临床试验提供信息。