Development of a small-molecule immunomodulator for the treatment of melanoma

开发治疗黑色素瘤的小分子免疫调节剂

• 批准号: 10379630
• 负责人: Rukiyah Van Dross
• 金额: $ 39.82万
• 依托单位: CLARADELE PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379630
• 关键词: Adverse effects; Biological; Body Weight; C57BL/6 Mouse; CD8-Positive T-Lymphocytes; CD8B1 gene; CTLA4 gene; Cancer cell line; Cessation of life; Collaborations; Colon Carcinoma; Dacarbazine; Data; Dendritic Cells; Dendritic cell activation; Dendritic cell tumor; Development; Dose; Enhancers; Evaluation; Exhibits; Exposure to; Formulation; Fostering; Foundations; Goals; Growth; Human; Immune; Immune checkpoint inhibitor; Immunoglobulin G; Immunologic Adjuvants; Immunomodulators; Immunotherapeutic agent; Immunotherapy; In Vitro; In complete remission; Incidence; Individual; Infiltration; Inflammation; Investigation; Knowledge; Legal patent; Lesion; Life; Ligands; MEKs; Mediating; Memory; Methods; Molecular; Mus; Mutation; PD-1 blockade; PD-1/PD-L1; Patients; Pattern; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology and Toxicology; Phase; Property; Proto-Oncogenes; Receptor Cell; Regimen; Regulatory T-Lymphocyte; Resistance; Resistance development; Role; Route; Savings; Skin Cancer; Small Business Technology Transfer Research; Solid Neoplasm; Surface; Survival Rate; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Toxic effect; Toxicology; Treatment Cost; Tumor Antigens; advanced disease; anti-PD-1; anti-PD1 antibodies; base; cancer cell; cytotoxic; density; dosage; endoplasmic reticulum stress; immune checkpoint blockade; improved; ineffective therapies; inhibitor; intraperitoneal; melanocyte; melanoma; mouse model; mutant; neoplastic cell; novel; oxaliplatin; partial response; pharmacokinetics and pharmacodynamics; preclinical development; programmed cell death protein 1; recruit; response; small molecule; subcutaneous; targeted agent; treatment duration; treatment group; treatment response; tumor; tumorigenic

SUMMARY Melanoma is the most lethal form of skin cancer with treatment costs exceeding $3 billion each year. Melanoma is successfully managed at early stages however, five-year survival rates for the advanced disease are as low as 20%. Immunotherapeutic checkpoint inhibitors (ICI) including agents that target PD1/PD-L1, have substantially improved melanoma survival rates. Unfortunately, only 35-60% of melanoma patients exhibit complete or partial responses to ICIs. Moreover, melanoma tumors that have mutations in the Braf protooncogene rapidly develop resistance to Braf/MEK inhibitors. Few treatment options remain for patients who fail to respond to ICIs or have developed resistance to Braf inhibitors. To prolong the lives of these individuals, optimized ICI regimens that are effective in ICI- and Braf-resistant melanoma are urgently needed. Claradele Pharmacetuicals is investigating whether pretreating melanoma with the novel, small molecule immunostimulatory endoplasmic reticulum (ER) stress inducer, 15dPMJ2, will sensitize the lesions to PD1 blockade. Our data demonstrate that 15dPMJ2 inhibited subcutaneous melanoma growth. In addition, 15dPMJ2 increased the tumor infiltration of active dendritic and memory T cells. Studies in this project will define doses of 15dPMJ2 that are safe to administer with anti-PD1 by determining the optimal biological dose (OBD). We will also test whether generating tumor inflammation with intratumorally administered 15dPMJ2 increases the rate at which melanoma responds to PD1 blockade. Our syngeneic murine models will be used to examine the effects of 15dPMJ2 on melanoma that contains or is devoid of human driver Braf mutations. Accomplishing our goals will provide proof-of-concept that optimizing the activity of ICIs with 15dPMJ2 will allow a significant proportion of melanoma patients to benefit from these life-saving therapeutics. The knowledge gained from this investigation will form the foundation of a Phase II STTR application that will examine agent formulation, optimize medicinal chemistry parameters, develop a CMC package, and define key toxicology and pharmacology properties of 15dPMJ2 to support an IND submission to the FDA.

摘要 黑色素瘤是最致命的皮肤癌，每年的治疗费用超过30亿美元。 黑色素瘤在早期治疗成功，但晚期黑色素瘤的五年存活率 低至20%。免疫治疗性检查点抑制剂(ICI)，包括靶向PD1/PD-L1的药物， 大大提高了黑色素瘤的存活率。不幸的是，只有35-60%的黑色素瘤患者表现出 对ICIS的全部或部分回应。此外，具有BRAF突变的黑色素瘤 原癌基因迅速对BRAF/MEK抑制剂产生耐药性。留给患者的治疗选择寥寥无几 对ICIS无反应或对BRAF抑制剂产生抗药性。为了延长这些生物的寿命 对于个体来说，迫切需要对ICI和BRAF耐药黑色素瘤有效的优化ICI方案。 Claradele制药公司正在研究是否可以用这种新的小分子来预处理黑色素瘤 免疫刺激内质网应激诱导剂15dPMJ2将使皮损对PD1增敏 封锁。我们的数据显示15dPMJ2抑制皮下黑色素瘤的生长。此外, 15dPMJ2可增加肿瘤内活性树突状细胞和记忆T细胞的浸润。该项目的研究将 通过确定15dPMJ2的最佳生物剂量，确定与抗PD1一起安全使用的剂量 (OBD)。我们还将测试瘤内注射15dPMJ2是否会产生肿瘤炎症 增加黑色素瘤对PD1阻滞剂的反应率。我们的同基因小鼠模型将用于 检测15dPMJ2对含有或不含人类驱动基因BRAF突变的黑色素瘤的影响。 实现我们的目标将提供概念证明，即使用15dPMJ2优化ICIS的活动将 让相当大比例的黑色素瘤患者从这些挽救生命的疗法中受益。这个 从这次调查中获得的知识将构成第二阶段STTR应用的基础，该应用将 检查试剂配方，优化药物化学参数，开发CMC包，并确定关键 15dPMJ2的毒理学和药理学特性，以支持IND向FDA提交。