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:
  • 金额:
    --
  • 依托单位:
  • 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

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,我们的退伍军人患这种疾病的风险更高

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Micrometastatic Dormancy in Uveal Melanoma: A Comprehensive Review of the Evidence, Mechanisms, and Implications for Future Adjuvant Therapies.
葡萄膜黑色素瘤的微转移休眠:对未来辅助治疗的证据、机制和影响的全面回顾。
  • DOI:
    10.1097/iio.0000000000000160
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Nichols,ErinE;Richmond,Ann;Daniels,AnthonyB
  • 通讯作者:
    Daniels,AnthonyB
4-(1H-Tetra-zol-5-yl)-1H-indole.
4-(1H-四唑-5-基)-1H-吲哚。
Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer.
  • DOI:
    10.3390/ijms22105207
  • 发表时间:
    2021-05-14
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
    Yan C;Yang J;Saleh N;Chen SC;Ayers GD;Abramson VG;Mayer IA;Richmond A
  • 通讯作者:
    Richmond A
LASP-1: a nuclear hub for the UHRF1-DNMT1-G9a-Snail1 complex.
  • DOI:
    10.1038/onc.2015.166
  • 发表时间:
    2016-03-03
  • 期刊:
  • 影响因子:
    8
  • 作者:
    Duvall-Noelle N;Karwandyar A;Richmond A;Raman D
  • 通讯作者:
    Raman D
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Ann Richmond其他文献

Ann Richmond的其他文献

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{{ truncateString('Ann Richmond', 18)}}的其他基金

BLR&D Merit Review Research Career Scientist (RCS) Award (IK6)
BLR
  • 批准号:
    10618231
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
BLR&D Merit Review Research Career Scientist (RCS) Award (IK6)
BLR
  • 批准号:
    10454101
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Optimizing Response to Immune Checkpoint Inhibitor Therapy for Breast Cancer: A Role for Inhibitors of the PI3K pathway
优化乳腺癌免疫检查点抑制剂治疗的反应:PI3K 通路抑制剂的作用
  • 批准号:
    10305634
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Optimizing Response to Immune Checkpoint Inhibitor Therapy for Breast Cancer: A Role for Inhibitors of the PI3K pathway
优化乳腺癌免疫检查点抑制剂治疗的反应:PI3K 通路抑制剂的作用
  • 批准号:
    9916443
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Optimizing Response to Immune Checkpoint Inhibitor Therapy for Breast Cancer: A Role for Inhibitors of the PI3K pathway
优化乳腺癌免疫检查点抑制剂治疗的反应:PI3K 通路抑制剂的作用
  • 批准号:
    10531596
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
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
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Modeling New Therapeutic Approaches for Malignant Melanoma
模拟恶性黑色素瘤的新治疗方法
  • 批准号:
    8817140
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Modeling New Therapeutic Approaches for Malignant Melanoma
模拟恶性黑色素瘤的新治疗方法
  • 批准号:
    8633274
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
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:
    10265337
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Modeling New Therapeutic Approaches for Malignant Melanoma
模拟恶性黑色素瘤的新治疗方法
  • 批准号:
    8966669
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:

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