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

使用 HDAC 抑制剂 SNDX-275 增强肾细胞癌对 IL-2 的反应

• 批准号: 7656978
• 负责人: Roberto Pili
• 金额: $ 34.65万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7656978
• 关键词: Anatomy; Antitumor Response; Benzamides; Biological; Biometry; CD8B1 gene; Cancer Therapy Evaluation Program; Cells; Clear Cell; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Combined Modality Therapy; Couples; Development; Disease remission; Dose; Exposure to; Foundations; Future; Gene Expression Regulation; Goals; Grant; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Image; Immune; Immune response; Immune system; Immunology; Immunomodulators; Immunotherapy; Interleukin-2; Lymphoma; Malignant Neoplasms; Metabolism; Metastatic Renal Cell Cancer; Modeling; Mus; Natural Killer Cells; PET/CT scan; Pathology; Patients; Pharmacodynamics; Phase; Phase II/III Trial; Pre-Clinical Model; Property; Regulation; Renal Cell Carcinoma; Renal carcinoma; Research; Research Personnel; Role; Solid Neoplasm; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Translating; Treatment Protocols; Tumor Biology; Work; cancer therapy; design; drug development; immunogenic; innovation; insight; interest; lymph nodes; medical schools; mouse model; novel; novel therapeutics; pre-clinical; public health relevance; response; tumor; urologic

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.

描述（由申请人提供）：高剂量白介素2 （IL-2）是一种被批准的治疗转移性肾细胞癌（RCC）的方案。不幸的是，反应率是适度的，只有少数患者实现持久的缓解。我们需要针对增强IL-2抗肿瘤作用的治疗。组蛋白去乙酰化酶（HDAC）抑制剂是一类通过转录和非转录基因调控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，已在临床前模型（包括RCC）中显示出抗肿瘤活性，目前正处于临床开发阶段。我们的初步结果表明，SNDX-275在小鼠RCC模型中与高剂量IL-2协同作用，并且治疗与肿瘤区域淋巴结中调节性T细胞的减少有关。本研究的主要目的是确定HDAC抑制剂治疗RCC的新联合策略调节免疫反应的治疗潜力。我们的中心假设是：1)靶向HDAC在RCC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；3)有必要对RCC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RCC患者特异性免疫细胞中的作用；2)确定HDAC抑制剂和IL-2在小鼠模型中的成功联合是否转化为RCC患者的临床获益。我们将在晚期透明细胞RCC患者中使用SNDX-275联合高剂量IL-2进行I/II期研究。这项研究是一项合作的成果。这是一项由研究者发起的癌症治疗和评估项目赞助的研究，临床方面由约翰霍普金斯大学U01基金支持。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RCC患者免疫细胞的生物学效应。具体目标2：评估联合使用SNDX-275和IL-2的临床反应预测因素。这些研究意义重大，因为它们代表了HDAC抑制剂通过利用其对免疫系统的潜在调节而合理组合的发展。我们期望这些研究将提供1)早期临床证据，证明HDAC抑制剂和免疫调节剂联合使用可以提高抗肿瘤效果；2)深入了解HDAC在调节特定T淋巴细胞亚型中的作用；3)为未来在RCC和其他免疫原性肿瘤中的临床试验奠定基础。公共卫生相关性：我们的团队对开发泌尿系统恶性肿瘤患者的合理联合疗法感兴趣，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——组蛋白去乙酰化酶抑制剂的抗肿瘤作用的理解，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。