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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：iPilimumab，Nivolumab和Pembrolizumab的最新FDA批准，它们靶向检查点受体细胞毒性T淋巴细胞相关的抗原-4（CTLA-4）（CTLA-4）和程序性死亡1（PD-1）（PD-1），在癌症免疫疗法的新时代中使用了转移性糖浆瘤的新时代。尽管联合疗法的前所未有的总体生存益处，但完全反应的事件仅为12-22％，与免疫相关的不良事件（IRAE）增加了，治疗成本每年每年每年275,000美元。因此，不仅需要转移性黑色素瘤，而且还需要更具遗传稳定的实体瘤，以提高检查点阻断的安全性和有效性的成本效益方法。细胞粘附整合素VLA-4和LFA-1是有效的抗原表现，运输和效应细胞肿瘤活性所必需的。这些整合素受体是自身免疫性疾病的临床验证治疗靶标；抑制剂（如纳塔省）降低了T细胞的激活和迁移。相反，我们发现了小分子整合素激动剂，例如7HP349，这可能会提高免疫激素对实体瘤的效率。与免疫检查点封锁结合使用时，这种方法可能特别有用。我们的初步数据表明，7HP349可能会增加天然杀伤细胞的肿瘤性活性，并且在转移性黑色素瘤的合成性攻击模型中，检查点阻断的抗肿瘤活性可能显着增加。我们在该提案中的工作假设是，整联蛋白激动剂7HP349可能在既定的转移性黑色素瘤治疗模型中可能会产生检查点阻断的抗肿瘤效应。在特定的目标1中，我们计划单独评估7HP349的影响，并结合检查点阻断对结核和调节细胞的总生存率，肿瘤生长以及肿瘤浸润的总体生存率。在特定目标2中，我们计划通过药代动力学分析进一步优化7HP349的剂量和时间表，并评估包括伊拉斯在内的一般毒理学。在将来的II期STTR工作中，我们计划在其他肿瘤模型（例如前列腺）中评估该化合物，这在历史上一直是难治性的检查点封锁。此外，我们计划启动GMP制造，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估”中一致的深入安全分析。成功完成拟议的药物开发计划可能会导致对7HP349的研究新药物应用，这是一种新型的小分子免疫调节剂，用于治疗实体瘤。