Enhancing renal cell carcinoma response to IL-2 with the HDAC inhibitor SNDX-275

描述(由申请人提供)：高剂量白介素2(IL-2)是转移性肾细胞癌(RCC)的批准方案。不幸的是，缓解率不高，只有少数患者获得持久缓解。需要以增强IL-2的抗肿瘤作用为目的的治疗。组蛋白脱乙酰酶(HDAC)抑制剂是一类通过转录和非转录基因调控而具有抗肿瘤活性的新型药物。SNDX-275是一种苯甲酰胺HDAC抑制剂，已被证明在包括肾癌在内的临床前模型中具有抗肿瘤活性，目前正在临床开发中。我们的初步结果表明，SNDX-275与大剂量IL-2在小鼠肾癌模型中具有协同作用，其治疗与肿瘤区域淋巴结中调节性T细胞的减少有关。这项研究的主要目的是确定使用HDAC抑制剂的新组合策略来调节免疫反应治疗肾癌的治疗潜力。我们的中心假设是：1)靶向HDAC在肾癌中显示出临床前和临床活性；2)HDAC抑制剂通过调节特定的T淋巴细胞亚群具有免疫调节特性；以及3)有必要对肾癌实施免疫治疗。为此，我们将追求以下目标：1)确定HDAC抑制剂在调节肾癌患者特定免疫细胞中的作用；2)确定HDAC抑制剂与IL-2在小鼠模型中的成功结合是否能为肾癌患者带来临床益处。我们将用SNDX-275联合大剂量IL-2对晚期透明细胞肾癌患者进行I/II期研究。这项研究代表了一项合作努力。这是一项由研究人员发起、癌症治疗和评估计划赞助的研究，其中临床方面得到了约翰霍普金斯大学U01拨款的支持。我们建议通过追求以下特定目标来验证我们的中心假设：特定目标#1：评估SNDX-275和IL-2对肾癌患者免疫细胞的生物学效应。具体目标2：评估SNDX-275和IL-2联合应用对临床疗效的预测作用。这些研究意义重大，因为它们代表了通过开发HDAC抑制剂对免疫系统的潜在调节而开发出合理的组合。我们期望这些研究将提供1)联合使用HDAC抑制剂和免疫调节剂可增强抗肿瘤作用的早期临床证据，2)深入了解HDAC在调节特定T淋巴细胞亚型中的作用，以及3)为未来肾癌和其他免疫原性肿瘤的临床试验奠定基础。公共卫生相关性：我们小组对为泌尿系恶性肿瘤患者开发合理的联合疗法感兴趣，长期目标是在II-III期临床研究中测试这些联合疗法。这一建议是相关的，因为它将促进我们对一类新型治疗药物组蛋白脱乙酰酶抑制剂的抗肿瘤作用的了解，并有助于设计合理的组合，用于治疗肾癌和其他实体肿瘤的临床试验。

DESCRIPTION (provided by applicant): High dose interleukin 2 (IL-2) is an approved regimen for metastatic renal cell carcinoma (RCC). Unfortunately, the response rate is modest and only few patients achieve durable remission. Treatments aimed to enhance the antitumor effect of IL-2 are needed. Histone deacetylase (HDAC) inhibitors represent a novel class of agents with antitumor activity by both transcriptional and non- transcriptional gene regulation. SNDX-275, a benzamide HDAC inhibitor, has been shown to have antitumor activity in preclinical models including RCC and is currently in clinical development. Our preliminary results have shown that SNDX-275 synergizes with high dose IL-2 in a murine model of RCC and the treatment was associated with reduction of regulatory T cells in tumor regional lymph nodes. The principal objective of the proposed research is to determine the therapeutic potential of modulating immune response with novel combination strategies involving HDAC inhibitors for the treatment of RCC. Our central hypotheses are that 1) targeting HDAC has shown preclinical and clinical activity in RCC; 2) HDAC inhibitors have immunomodulatory properties by regulating specific subsets of T lymphocytes; and 3) there is a need to implement immunotherapies for RCC. To this end we will pursue the following goals: 1) to define the role of HDAC inhibitor in regulating specific immune cells in patients with RCC; 2) to determine whether the successful combination of an HDAC inhibitor and IL-2 in a mouse model translates into clinical benefit for RCC patients. We will conduct a phase I/II study with SNDX-275 in combination with high dose IL-2 in patients with advanced clear cell RCC. This study represents a collaborative effort. It is an investigator initiated, Cancer Therapy and Evaluation Program sponsored study where the clinical aspects are supported by the Johns Hopkins U01 grant. We propose to test our central hypotheses by pursuing the following Specific Aims: Specific Aim #1: To assess the biological effects of SNDX-275 and IL-2 on immune cells in RCC patients. Specific Aim #2: To assess predictors of clinical response with the combination of SNDX-275 and IL-2. These studies are significant because they represent the development of a rational combination of HDAC inhibitors by exploiting their potential regulation of the immune system. We expect that these studies will provide 1) early clinical evidence that combining HDAC inhibitors and immunomodulators increases the antitumor effects, 2) insight on the role of HDACs in the modulations of specific T lymphocyte subtypes, and 3) the foundation for future clinical trials in RCC and other immunogenic tumors. PUBLIC HEALTH RELEVANCE: Our group is interested in the development of rational combination therapies for patients with urological malignancies with the long-term goal of testing these combinations in phase II-III clinical studies. This proposal is relevant because it will advance our understanding of the antitumor effect of a novel class of therapeutic agents, the histone deacetylase inhibitors, and help to design rational combinations to be tested in clinical trials for the treatment of kidney cancer and other solid tumors.