Combined ATRA and ipilimumab treatment to reduce immunosuppression in melanoma patients

ATRA 和伊匹单抗联合治疗可减少黑色素瘤患者的免疫抑制

• 批准号: 9098660
• 负责人: MARTIN MCCARTER
• 金额: $ 16.91万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9098660
• 关键词: Acute Promyelocytic Leukemia; Adverse event; Aftercare; Autoimmunity; Biological Assay; Cancer Immunology Science; Cancer Vaccines; Cell Lineage; Cells; Cessation of life; Clinical; Clinical Chemistry; Combined Modality Therapy; Cytotoxic T-Lymphocyte-Associated Protein 4; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Diagnosis; Disease Progression; Drug Targeting; Effector Cell; FDA approved; Flow Cytometry; Frequencies; Future; Goals; Health; Hematology; Human; Imaging Techniques; Immature Monocyte; Immune; Immune response; Immune system; Immunity; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; In complete remission; Incidence; Infection prevention; Infusion procedures; Laboratories; Malignant Neoplasms; Methods; Monitor; Myelogenous; Outcome; Patient Monitoring; Patients; Pharmaceutical Preparations; Phase; Pilot Projects; Randomized Clinical Trials; Regulatory T-Lymphocyte; Research; Risk; Staging; Suppressor-Effector T-Lymphocytes; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Treatment Protocols; Tretinoin; Tumor Antigens; Tumor Markers; United States; Vitamin A; advanced disease; cancer immunotherapy; cancer therapy; combinatorial; effective therapy; improved; improved outcome; innovation; melanoma; neoplastic cell; peripheral blood; phenotypic biomarker; potential biomarker; prevent; response; standard care; success; tumor

 DESCRIPTION (provided by applicant): Melanoma remains a large burden in the United States due to both its rising incidence and the lack of success in preventing melanoma-related death in people diagnosed with more advanced disease. It is a unique tumor in humans for its ability to elicit profound immune responses and for its sensitivity to treatments that target the immune system. As such, melanoma represents the ideal tumor for research in cancer immunology, particularly for studying the mechanisms by which tumors usurp the effector immune system and avoid current therapies. Recently, myeloid-derived suppressor cells (so-called MDSCs) have been implicated as key contributors in immune evasion by tumor cells. These cells suppress immune responses to cancer and limit the benefits of certain cancer treatments, such as cancer vaccines and immunotherapy. Currently available immunotherapies, such as anti-CTLA-4 (ipilimumab), could potentially be improved by reducing the frequency or activity of MDSCs. We propose that treatment with all-trans retinoic acid (ATRA), a derivative of vitamin A known to differentiate suppressive MDSCs into stimulatory dendritic cells, will decrease immunosuppression thereby increasing tumor-specific immunity. We hypothesize that combined treatment with ATRA and ipilimumab will 1) be safe and tolerable, 2) reduce the frequency and/or function of MDSCs in advanced-stage melanoma patients, and 3) increase the frequency and/or activation of tumor-specific T cell responses. This combined treatment tests the paradigm that overall response rates will be improved by simultaneously targeting effector cells and suppressor cells. Furthermore, by specifically targeting immunosuppressive MDSCs, this will be the first study to evaluate whether a reduction in MDSCs positively impacts disease progression in human melanoma patients. The aims of our proposal will test these hypotheses using the following methods: In aim 1, we will follow standard treatment protocols for ipilimumab to monitor patients with and without ATRA for adverse events. In aim 2, we will monitor the frequency and function of MDSCs in the peripheral blood throughout the course of treatment using flow cytometry and T cell suppression assays. In aim 3, we will use flow cytometry and T cell stimulation assays to monitor the frequency of T cell subsets, expression of activation markers, and tumor-specific T cell responses throughout the course of treatment. We will also monitor clinical disease progression and overall survival of treated patients. In summary, this innovative pilot study will determine if combinatorial treatment with ATRA and ipilimumab is safe and potentially effective for the treatment of Stage IV melanoma patients.

 描述（由申请人提供）：黑色素瘤在美国仍然是一个很大的负担，因为它的发病率不断上升，而且在预防被诊断患有更晚期疾病的人的黑色素瘤相关死亡方面缺乏成功。它是人类中独特的肿瘤，因为它能够引起深刻的免疫反应，并且对靶向免疫系统的治疗敏感。因此，黑色素瘤代表了癌症免疫学研究的理想肿瘤，特别是对于研究肿瘤篡夺效应免疫系统并避免当前疗法的机制。最近，骨髓来源的抑制细胞（所谓的MDSC）已被牵连作为肿瘤细胞免疫逃逸的关键贡献者。这些细胞抑制对癌症的免疫反应，并限制某些癌症治疗的益处，如癌症疫苗和免疫疗法。目前可用的免疫疗法，如抗CTLA-4（伊匹单抗），可能通过降低MDSC的频率或活性来改善。我们提出，全反式维甲酸（ATRA），维生素A的衍生物，已知分化成刺激性树突状细胞的抑制MDSC的治疗，将减少免疫抑制，从而增加肿瘤特异性免疫。我们假设ATRA和易普利姆玛的联合治疗将1）安全且可耐受，2）降低晚期黑色素瘤患者中MDSC的频率和/或功能，3）增加肿瘤特异性T细胞应答的频率和/或激活。这种联合治疗测试了通过同时靶向效应细胞和抑制细胞将提高总体应答率的范例。此外，通过特异性靶向免疫抑制性MDSC，这将是第一项评估MDSC减少是否对人类黑色素瘤患者的疾病进展产生积极影响的研究。我们的提案的目的将使用以下方法测试这些假设：在目的1中，我们将遵循ipilimumab的标准治疗方案，以监测有和没有ATRA的患者的不良事件。在目标2中，我们将使用流式细胞术和T细胞抑制测定法监测整个治疗过程中外周血中MDSC的频率和功能。在目标3中，我们将使用流式细胞术和T细胞刺激试验来监测整个治疗过程中T细胞亚群的频率、活化标志物的表达和肿瘤特异性T细胞应答。我们还将监测治疗患者的临床疾病进展和总生存期。 总之，这项创新的试点研究将确定ATRA和易普利姆玛的联合治疗是否安全，并可能有效地治疗IV期黑色素瘤患者。