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

DESCRIPTION provided by applicant Recent FDA approvals of ipilimumab nivolumab and pembrolizumab which target checkpoint receptors cytotoxic T lymphocyte associated antigen CTLA and programmed death PD 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 immune related adverse events irAEs are increased and the cost of treatment is approaching $ 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 and LFA 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 HP 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 HP 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 HP can potentiate the anti tumor effects of checkpoint blockade in an established therapeutic model of metastatic melanoma In Specific Aim we plan to evaluate the effects of HP alone and in combination with checkpoint blockade on overall survival tumor growth and tumor infiltration of tumoricidal and regulatory cells In specific Aim we plan to further optimize dose and schedule of HP 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 andquot Guidance for Industry S Nonclinical evaluation of anticancer pharmaceuticals andquot Successful completion of the proposed drug development program could lead to filing of an Investigational New Drug Application for HP a novel small molecule immunomodulator for the treatment of solid tumors

PUBLIC HEALTH RELEVANCE Recent advances in unlocking the bodyandapos s own defense mechanisms checkpoint blockade in the fight against cancer have been revolutionizing the cancer field We have identified a small molecule drug candidate that has the potential to activate the endogenous immune response to cancer If demonstrated to be safe and effective our approach could provide a novel and cost effective means to enhance the therapeutic efficacy of currently approved and future checkpoint receptor inhibitors