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

Recent FDA approvals of ipilimumabnivolumaband pembrolizumabwhich target checkpoint receptors cytotoxic T lymphocyte associated antigenCTLAand programmed deathPDhave ushered in a new era of cancer immunotherapy in metastatic melanomaDespite unprecedented overall survival benefits with combination therapythe incidence of complete responses are onlyimmune related adverse eventsirAEsare increasedand the cost of treatment is approaching $per patient per yearAs suchcost effective approaches to improve the safety and effectiveness of checkpoint blockade for not only metastatic melanomabut also for more genetically stable solid tumors are neededCell adhesion integrins VLAand LFAare required for efficient antigen presentationtraffickingand tumoricidal activity of effector cellsThese integrin receptors are clinically validated therapeutic targets in autoimmune diseaseinhibitors such as natalizumab decrease T cell activation and migrationConverselywe have discovered small molecule integrin agonistsegHPthat may increase the efficiency of the immune response against solid tumorsThis approach could be particularly useful when combined with immune checkpoint blockadeCompleted phase I studies have demonstrated thatHPcan significantly enhance the anti tumor activity of anti CTLAanti PDand antiBB antibodies in animal models of melanoma and carcinomaToxicity studies have demonstrated the compound to be safeeven when administered at doses up tofold higher that it s therapeutic doseBased on this successour current phase II effort is centered around in vivo testing of oral administration ofHPin the BBLmelanoma modelmechanistic studies to guide biomarker developmentincluding the effects ofHPon T effector cell biodistributionSpecifc AimGLP INDenabling studies of toxicity in rodent and non rodent speciesincluding radiolabeled ADMESpecific Aimand an iterative synthetic chemistry approach to further optimize drug like characteristics of our lead candidateHPSpecific AimAll work proposed will be consistent with FDA guidelines outlined inGuidance for IndustrySNonclinical evaluation of anticancer pharmaceuticalsRecent advances in unlocking the bodyandapos s own defense mechanismscheckpoint blockadein the fight against cancer have been revolutionizing the cancer fieldWe have identified a small molecule drug candidate that has the potential to activate the endogenous immune response to cancerIf demonstrated to be safe and effectiveour approach could provide a novel and cost effective means to enhance the therapeutic efficacy of currently approvedand futurecheckpoint blockade inhibitors