Combined ATRA and ipilimumab treatment to reduce immunosuppression in melanoma patients

 描述(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，而且在预防被诊断为更晚期疾病的人中与黑色素瘤相关的死亡方面缺乏成功。它在人类中是一种独特的肿瘤，因为它能够引发深刻的免疫反应，并且对针对免疫系统的治疗敏感。因此，黑色素瘤是癌症免疫学研究的理想肿瘤，特别是研究肿瘤侵占效应免疫系统和避免目前治疗的机制。最近，髓系来源的抑制细胞(所谓的MDSCs)被认为是肿瘤细胞免疫逃避的关键因素。这些细胞抑制对癌症的免疫反应，并限制某些癌症治疗的好处，如癌症疫苗和免疫治疗。目前可用的免疫疗法，如抗CTLA-4(Ipilimumab)，可能会通过降低MDSCs的频率或活性来改进。我们认为，全反式维甲酸(ATRA)是一种维生素A的衍生物，可将抑制性MDSCs分化为刺激性树突状细胞，将减少免疫抑制，从而提高肿瘤特异性免疫。我们假设，ATRA和ipilimumab的联合治疗将1)安全和可耐受，2)减少晚期黑色素瘤患者MDSCs的频率和/或功能，3)增加肿瘤特异性T细胞反应的频率和/或激活。这种联合治疗测试了这样一种范式，即通过同时靶向效应细胞和抑制细胞，总体应答率将得到提高。此外，通过专门针对免疫抑制的MDSCs，这将是第一个评估MDSCs减少是否对人类黑色素瘤患者的疾病进展有积极影响的研究。我们提案的目的将使用以下方法验证这些假设：在目标1中，我们将遵循ipilimumab的标准治疗方案，以监测服用和不服用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细胞抑制分析来监测治疗过程中外周血中MDSCs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、激活标志物的表达以及肿瘤特异性T细胞反应。我们还将监测临床疾病进展和接受治疗的患者的总体存活率。总之，这项创新的先导研究将确定ATRA和ipilimumab联合治疗IV期黑色素瘤患者是否安全和潜在有效。

 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.