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

点击翻译按钮获取中文摘要

 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.