Development of a small molecule activator of integrin cell adhesion to enhance therapeutic responses to checkpoint blockade in cancer

开发整合素细胞粘附小分子激活剂以增强癌症检查点阻断的治疗反应

• 批准号: 9138564
• 负责人: Upendra Marathi
• 金额: $ 31.37万
• 依托单位: 7 HILLS PHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-07 至 2018-04-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9138564
• 关键词: Address; Adjuvant; Adverse effects; Adverse event; Agonist; Animals; Antigen Presentation; Antigens; Autoimmune Diseases; Autoimmune Process; C57BL/6 Mouse; Cell Adhesion; Cell Adhesion Molecules; Cell Line; Cells; Cessation of life; Chemotaxis; Combined Modality Therapy; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Defense Mechanisms; Development; Dose; Drug Kinetics; Drug effect disorder; Effectiveness; Effector Cell; Evaluation; Extravasation; Future; GVAX Cancer Vaccine; Granulocyte-Macrophage Colony-Stimulating Factor; Guidelines; Immune; Immune Targeting; Immune response; Immune system; Immunomodulators; Immunotherapy; In complete remission; Incidence; Industry; Infiltration; Integrin alpha4beta1; Integrins; Investigational New Drug Application; Lead; Lymphocyte; Malignant Neoplasms; Melanoma Cell; Metastatic Melanoma; Methods; Modeling; Mus; Natural Killer Cells; Organ; PDCD1LG1 gene; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Pilot Projects; Plasma; Play; Prostate; Refractory; Research Design; Risk; Role; Safety; Schedule; Side; Signal Transduction; Small Business Technology Transfer Research; Solid Neoplasm; Subcutaneous Injections; Survival Rate; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Toxicology; Treatment Cost; Treatment Efficacy; Tumor Burden; Tumor Immunity; Vaccines; Validation; Work; analytical method; antitumor effect; base; cancer immunotherapy; cancer therapy; cost; cost effective; drug candidate; drug development; efalizumab; fight against; immunotoxicity; improved; in vivo; inhibitor/antagonist; innovation; insight; killings; melanoma; method development; migration; mouse model; natalizumab; novel; phrases; pre-clinical; programs; public health relevance; receptor; response; safety study; small molecule; subcutaneous; therapeutic effectiveness; therapeutic target; therapy design; trafficking; treatment response; tumor; tumor growth

 DESCRIPTION (provided by applicant): Recent FDA approvals of ipilimumab, nivolumab, and pembrolizumab, which target checkpoint receptors cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), have ushered in a new era of cancer immunotherapy in metastatic melanoma. Despite unprecedented overall survival benefits with combination therapy, the incidence of complete responses are only 12-22%, immune-related adverse events (irAEs) are increased, and the cost of treatment is approaching $275,000 per patient per year. As such, cost-effective approaches to improve the safety and effectiveness of checkpoint blockade for not only metastatic melanoma, but also for more genetically stable solid tumors are needed. Cell adhesion integrins VLA-4 and LFA-1 are required for efficient antigen presentation, trafficking, and tumoricidal activity of effector cells. These integrin receptors are clinically validated therapeutic targets in autoimmune disease; inhibitors such as natalizumab decrease T-cell activation and migration. Conversely, we have discovered small molecule integrin agonists, e.g., 7HP349, that may increase the efficiency of the immune response against solid tumors. This approach could be particularly useful when combined with immune checkpoint blockade. Our preliminary data suggests 7HP349 may increase the tumoricidal activity of natural killer cells and may significantly increase the antitumor activity of checkpoin blockade in a syngeneic aggressive model of metastatic melanoma. Our working hypothesis in this proposal is that integrin agonist 7HP349 can potentiate the anti- tumor effects of checkpoint blockade in an established therapeutic model of metastatic melanoma. In Specific Aim 1, we plan to evaluate the effects of 7HP349 alone and in combination with checkpoint blockade on overall survival, tumor growth, and tumor infiltration of tumoricidal and regulatory cells. In specific Aim 2, we plan to further optimize dose and schedule of 7HP349 through pharmacokinetic analysis, and evaluate general toxicology including irAEs. In future Phase II STTR effort, we plan to evaluate the compound in additional tumor models, such as prostate, which has historically been refractory to checkpoint blockade. Moreover, we plan to initiate IND-enabling GMP manufacture, larger scale animal studies, and in-depth safety analyses consistent with FDA guidelines in "Guidance for Industry: S9 Nonclinical evaluation of anticancer pharmaceuticals." Successful completion of the proposed drug development program could lead to filing of an Investigational New Drug Application for 7HP349, a novel small molecule immunomodulator for the treatment of solid tumors.

 描述（由申请人提供）：最近FDA批准的ipilimumab、nivolumab和pembrolizumab靶向检查点受体细胞毒性T淋巴细胞相关抗原-4（CTLA-4）和程序性死亡-1（PD-1），开创了转移性黑色素瘤癌症免疫治疗的新时代。尽管联合治疗带来了前所未有的总体生存益处，但完全缓解的发生率仅为12- 22%，免疫相关不良事件（irAE）增加，治疗费用接近每例患者每年275，000美元。因此，需要成本有效的方法来提高检查点阻断的安全性和有效性，不仅用于转移性黑色素瘤，而且用于遗传上更稳定的实体瘤。细胞粘附整联蛋白VLA-4和LFA-1是效应细胞的有效抗原呈递、运输和杀肿瘤活性所必需的。这些整合素受体是 自身免疫性疾病中临床验证的治疗靶点;抑制剂如那他珠单抗可降低T细胞活化和迁移。相反，我们已经发现了小分子整联蛋白激动剂，例如，7 HP 349，其可以增加针对实体瘤的免疫应答的效率。当与免疫检查点阻断结合时，这种方法可能特别有用。我们的初步数据表明，7 HP 349可能会增加自然杀伤细胞的杀肿瘤活性，并可能会显着增加在转移性黑色素瘤的同源侵袭性模型中的检查点阻断的抗肿瘤活性。我们在该提议中的工作假设是，整合素激动剂7 HP 349可以在转移性黑素瘤的已建立的治疗模型中增强检查点阻断的抗肿瘤作用。在具体目标1中，我们计划评估7 HP 349单独使用和与检查点阻断剂联合使用对总生存期、肿瘤生长以及杀肿瘤细胞和调节细胞的肿瘤浸润的影响。在具体目标2中，我们计划通过药代动力学分析进一步优化7 HP 349的剂量和给药方案，并评估包括irAE在内的一般毒理学。在未来的II期STTR工作中，我们计划在其他肿瘤模型中评估该化合物，例如前列腺，其历史上对检查点阻断难治。此外，我们计划启动IND支持的GMP生产，更大规模的动物研究，以及与FDA指南“行业指南：S9抗癌药物的非临床评价”一致的深入安全性分析。“成功完成拟议的药物开发计划可能会导致提交7 HP 349的研究性新药申请，这是一种用于治疗实体瘤的新型小分子免疫调节剂。