Development of 7HP349, an oral integrin activator to enhance therapeutic responses to immune checkpoint inhibitors

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PROJECT SUMMARY/ABSTRACT Immune checkpoint inhibitors (CPIs), such aPD-1 agents (nivolumab, and pembrolizumab), are the current standard of care treatment for the frontline management of advanced melanoma and other solid tumors. However, ~70% of patients with approved FDA indications do not respond. Importantly, once patients progress, there are limited treatment options. Primary and acquired resistance to checkpoint inhibitors may be due to the lack of immune effector cell priming and trafficking into tumor tissue. 7HP349 is a first-in-concept, oral, small molecule, positive allosteric activator of specific integrin cell adhesion molecules, VLA-4 and LFA-1, which are essential for generation of a cellular immune response against solid tumors. These integrins are critical for T cell priming and tumor infiltration, and have been shown necessary for the effectiveness of immune checkpoint inhibitors, as well as for T cell vaccines. 7HP349, as systemic drug, has shown enhancement of spontaneous anti-tumor immunity alone or in combination with CPIs. Based on its favorable preclinical profile, US Food and Drug Administration, Division of Oncology Products 3, has approved the 7HP349 IND to conduct the proposed Phase 1 first-in-human study to lay the foundation for future studies in cancer patients. cGMP drug substance and drug product have been developed for first-in-human studies. In this Direct to Phase II grant, we plan to assess the safety and tolerability, and determine the 7HP349 optimal pharmacokinetic dose (OPD) and optimal biologic dose (OBD) for improving immune checkpoint blockade by performing the first-in-human study in healthy volunteers. This proposed Phase I study will not only guide the future evaluation of 7HP349 to augment antigen presentation in solid tumor patients that have failed PD-1- based therapies for potential approval in refractory melanoma, but also lay the foundation for the potential use in increasing the effectiveness of infectious disease vaccines.