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.
Public Health Relevance Statement: Public Health Relevance: Recent advances in unlocking the body'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.
NIH Spending Category: Cancer; Immunization; Vaccine Related
Project Terms: Address; Adjuvant; Adverse effects; Adverse event; Agonist; analytical method; Animals; Antigen Presentation; Antigens; antitumor effect; Autoimmune Diseases; Autoimmune Process; base; C57BL/6 Mouse; cancer immunotherapy; cancer therapy; Cell Adhesion; Cell Adhesion Molecules; Cell Line; Cells; Cessation of life; Chemotaxis; Combined Modality Therapy; cost; cost effective; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Defense Mechanisms; Development; Dose; drug candidate; drug development; Drug effect disorder; Drug Kinetics; efalizumab; Effectiveness; Effector Cell; Evaluation; Extravasation; fight against; Future; Granulocyte-Macrophage Colony-Stimulating Factor; Guidelines; GVAX Cancer Vaccine; Immune; Immune response; Immune system; Immune Targeting; Immunomodulators; Immunotherapy; immunotoxicity; improved; In complete remission; in vivo; Incidence; Industry; Infiltration; inhibitor/antagonist; innovation; insight; Integrin alpha4beta1; Integrins; Investigational New Drug Application; Killings; Lead; Lymphocyte; Malignant Neoplasms; melanoma; Melanoma Cell; Metastatic Melanoma; method development; Methods; migration; Modeling; mouse model; Mus; natalizumab; Natural Killer Cells; novel; Organ; Pathway interactions; Patients; PDCD1LG1 gene; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Phase; phrases; Pilot Projects; Plasma; Play; pre-clinical; programs; Prostate; public health relevance; receptor; Refractory; Research Design; response; Risk; Role; Safety; safety study; Schedule; Side; Signal Transduction; Small Business Technology Transfer Research; small molecule; Solid Neoplasm; subcutaneous; Subcutaneous Injections; Survival Rate; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; therapeutic effectiveness; therapeutic target; therapy design; Toxicology; trafficking; Treatment Cost; Treatment Efficacy; treatment response; tumor; Tumor Burden; tumor growth; Tumor Immunity; Vaccines; Validation; Work