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.
Public Health Relevance Statement: Project narrative: Immune checkpoint inhibitor therapies are ineffective in ~70% of solid tumor patients potentially due inefficient immune priming. We have identified a first-in-concept integrin activator, 7HP349, which promotes antigen specific immune responses, and reverses resistance of checkpoint inhibitor in resistant mouse tumor models. 7HP349 has the potential to significantly increase response rates in patients progressing on immune checkpoint therapy.
Project Terms: absorption; Address; Adverse effects; Animal Model; Animals; anti-PD-1; anti-tumor immune response; Antigen Presentation; Antigens; Autoimmune Process; bak protein; base; Biological; Biological Assay; Biological Availability; Blood specimen; Calories; Cancer Patient; Canis familiaris; capsule; Cell Adhesion; Cell Adhesion Molecules; cell motility; Cells; checkpoint therapy; Clinical; clinical development; cohort; commercialization; Communicable Diseases; Cross-Over Studies; Crossover Design; CTLA4 gene; Cyclic GMP; CYP3A4 gene; data modeling; Development; Development Plans; Dose; drug efficacy; Drug Kinetics; Effectiveness; Effector Cell; Evaluation; Fasting; Fatty acid glycerol esters; first-in-human; Food; Formulation; Foundations; Future; Generations; Grant; Guidelines; healthy volunteer; Hepatic; Human; human study; Immune; immune checkpoint blockade; Immune checkpoint inhibitor; Immune response; immunotoxicity; improved; In Vitro; ineffective therapies; Infiltration; inhibitor/antagonist; Instruction; Integrin alpha4beta1; Integrin-mediated Cell Adhesion Pathway; Integrins; Intercellular adhesion molecule 1; Investigational Drugs; Investigational New Drug Application; Left; Leukocytes; Ligands; Lipids; meetings; melanoma; Metastatic Melanoma; Modeling; Monitor; Mus; National Comprehensive Cancer Network; Nivolumab; Normal tissue morphology; objective response rate; Oncology; Oral; Organ; Orphan Drugs; Patients; Pharmaceutical Preparations; pharmacokinetics and pharmacodynamics; Phase; phase 1 study; phase 2 testing; Plasma; pre-clinical; preclinical study; prevent; Price; programmed cell death protein 1; Randomized; Rattus; Refractory; Regimen; Resistance; response; risk minimization; Safety; Schedule; side effect; Small Business Technology Transfer Research; small molecule; Solid Neoplasm; standard of care; Study Subject; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Thyroid Function Tests; Tissues; Toxic effect; Toxicology; trafficking; treatment response; tumor; tumor growth; Tumor Immunity; Tumor Tissue; United States Food and Drug Administration; Vaccines; Vascular Cell Adhesion Molecule-1; Work
