Cancer immunotherapy activates the host immune system to seek and destroy cancer cells. Checkpoint inhibitors block immunosuppressive signals, thereby "releasing the brakes' of the immune system. Solid tumors, however, typically do not respond well to checkpoint inhibitors. They are only effective in the 20-30% patients with an already immunologically hot tumor. Thus, novel immunostimulant therapies aim to recruit immune cells to tumor tissue, turning cold tumors hot and working synergistically with checkpoint inhibitors. Immunostimulants that induce local immune-cell infiltration may induce an Abscopal effect and may increase responsiveness in patients that are resistant to checkpoint inhibitors. Unfortunately, immunostimulants often induce systemic immune-related adverse events (e.g., cytokine release syndrome), even when administered locally to tumor tissue. Most immunostimulants exhibit molecular properties promoting diffusion and systemic absorption (e.g., small molecular size, negative charge, high water solubility), This presents a major limitation as it leads to limited immune activation in the target tumor tissue after administration and immune-related adverse events. In this project, we will advance KIN-001 - a tumor-retentive formulation of the immunostimulant CpG designed to persist in tumor tissue thereby mitigating systemic immune-related adverse events and potentiating immune activity in the tumor microenvironment and draining lymph nodes. KIN-001 is a small volume nanosuspension for intratumoral injection comprised of commercially available glatiramer acetate (GA)(Copaxone®, approved for multiple sclerosis) complexed with CpG (immunostimulant). Through preliminarystudies of KIN-001, our group has demonstrated its efficacy in recruiting immune cells to the tumor without inducing significant systemic cytokines, and we have identified the optimal mass ratio of GA to CpG. This Phase I STTR study has three Specific Aims: In Specific Aim 1, we will complete an in-use stability study of different formulations of KIN-001 to demonstrate that KIN-001 is a stable composition and quality is maintained between preparation and injection into the tumor under anticipated conditions of use. Specific Aim 2 will focus on identifying the maximum tolerated dose of KIN-001 compared to CpG in a predominant immunotherapy mouse model. In Specific Aim 3, we will establish proof of mechanism by elucidating KIN-001's tumor retention and synergy potential when combined with anti-PD1, a checkpoint inhibitor. The long-term goal of this project is to commercialize KIN-001 as the first and only tumor-retentive immunostimulant with low toxicity for cancer patients that have palpable (i.e., injectable) solid tumors and are refractory to checkpoint inhibitors. KIN-001will improve efficacy of standard treatment (e.g., checkpoint inhibitors) with minimal side effects, leading to improved outcomes and survival.
Public Health Relevance Statement: Project narrative: Solid tumors typically do not respond well to checkpoint inhibitor immunotherapy and are only effective in a small portion of patients with an already immunologically "hot' tumor. In this project, we will develop the first and only tumor-retentive CpG immunostimulant for cancer patients that have palpable (i.e., injectable) solid tumors and are refractory to checkpoint inhibitors. This adjunct immunostimulant therapy will be delivered via intratumoral injection to improve the efficacy of checkpoint inhibitors with minimal side effects, leading to improved outcomes and survival in cancer patients.
Project Terms: absorption, Immunologic Adjuvants, Immunoactivators, Immunoadjuvants, Immunological Adjuvant, Immunopotentiators, Immunostimulants, immune adjuvant, Malignant Neoplasms, Cancers, Malignant Tumor, malignancy, neoplasm/cancer, Cations, Cells, Cell Body, Charge, Clinical Trials, Diagnosis, Diffusion, Exhibits, Extracellular Matrix, Cell-Extracellular Matrix, ECM, Future, Goals, Head and Neck Neoplasms, head and neck tumor, Immune system, allergic/immunologic body system, allergic/immunologic organ system, Immunotherapy, Immune mediated therapy, Immunologically Directed Therapy, immune therapeutic approach, immune therapeutic interventions, immune therapeutic regimens, immune therapeutic strategy, immune therapy, immune-based therapies, immune-based treatments, immuno therapy, Interferon Type II, Gamma interferon, IFN-Gamma, IFN-g, IFN-γ, IFNG, IFNγ, Interferon Gamma, Interferon-gamma, lFN-Gamma, Immune Interferon, Interleukin-2, Co-Stimulator, Costimulator, Epidermal Thymocyte Activating Factor, IL-2, IL2 Protein, Interleukin 2, Interleukin 2 Precursor, Interleukin II, Interleukine 2, Interleukine 2 Precursor, Interleukine II, Lymphocyte Mitogenic Factor, Mitogenic Factor, T cell growth factor, T-Cell Growth Factor, T-Cell Stimulating Factor, Thymocyte Stimulating Factor, Interleukin-6, B cell differentiation factor, B cell stimulating factor 2, B-Cell Differentiation Factor, B-Cell Differentiation Factor-2, B-Cell Stimulatory Factor-2, BCDF, BSF-2, BSF2, HPGF, Hepatocyte-Stimulating Factor, Hybridoma Growth Factor, IFN-beta 2, IFNB2, IL-6, IL6 Protein, MGI-2, Myeloid Differentiation-Inducing Protein, Plasmacytoma Growth Factor, interferon beta 2, Multiple Sclerosis, Disseminated Sclerosis, insular sclerosis, Mus, Mice, Mice Mammals, Murine, Necrotic, Necrosis, Patents, Legal patent, Patients, Peptides, Publishing, Safety, Cell Communication and Signaling, Cell Signaling, Intracellular Communication and Signaling, Signal Transduction Systems, Signaling, biological signal transduction, Signal Transduction, Suspension substance, Suspensions, Testing, cytokine, Injectable, Metastatic Neoplasm to the Lung, Metastasis to the Lung, Metastatic Tumor to the Lung, lung metastasis, metastasize to the lung, pulmonary metastasis, improved, Site, Clinical, Refractory, Phase, Blood Serum, Serum, uptake, anti-cancer immunotherapy, anticancer immunotherapy, immune-based cancer therapies, immunotherapy for cancer, immunotherapy of cancer, cancer immunotherapy, Solid Tumor, Solid Neoplasm, Copaxone, copolymer I, glatiramer acetate, copolymer 1, Immunological response, host response, immune system response, immunoresponse, Immune response, Infiltration, Malignant Cell, cancer cell, Breast Melanoma, Hour, Immunes, Immune, Complex, Event, subdermal, subcutaneous, Head and Neck, Head and neck structure, Tumor Tissue, palpable disease, Palpable, molecular size, particle, success, water solubility, zeta potential, tumor growth, synergism, Toxicities, Toxic effect, Structure, novel, Position, Positioning Attribute, Maximal Tolerated Dose, Maximally Tolerated Dose, Maximum Tolerated Dose, (TNF)-α, Cachectin, Macrophage-Derived TNF, Monocyte-Derived TNF, TNF, TNF A, TNF Alpha, TNF-α, TNFA, TNFα, Tumor Necrosis Factor, Tumor Necrosis Factor-alpha, TNF gene, CXCL1, GRO1, GROA, MGSA, SCYB1, CXCL1 gene, Modeling, Sampling, Property, Phase I Clinical Trials, Early-Stage Clinical Trials, Phase 1 Clinical Trials, phase I protocol, Pharmaceutical Agent, Pharmaceuticals, Pharmacological Substance, Pharmacologic Substance, Diameter, Caliber, CD11b, CR3A, ITGAM, MAC1A, MO1A, ITGAM gene, CD8, CD8B, CD8B1, LYT3, CD8B1 gene, Dose, Tumor Load, Tumor Burden, Data, Cancer Patient, Small Business Technology Transfer Research, STTR, Unresectable, Immunologics, Immunochemical Immunologic, Immunologic, Immunological, Immunologically, Preparation, Molecular, Development, developmental, Image, imaging, tumor microenvironment, cancer microenvironment, self assembly, design, designing, nanoparticle, nano particle, nano-sized particle, nanosized particle, Outcome, innovation, innovate, innovative, Resistance, resistant, mouse model, murine model, tumor, standard care, standard treatment, immune activation, Immune Cell Activation, CT26, CT-26, Formulation, improved outcome, checkpoint therapy, check point immunotherapy, check point inhibitor therapy, check point inhibitory therapy, check point therapy, checkpoint immunotherapy, checkpoint inhibitor therapy, checkpoint inhibitory therapy, immune check point therapy, immune checkpoint therapy, Immune checkpoint inhibitor, Checkpoint inhibitor, immune check point inhibitor, cytokine release syndrome, cytokine storm, recruit, immune-related adverse events, immune-mediated adverse events, Injections, Tumor-infiltrating immune cells, Immune infiltrates, T cell infiltration, T cell tumor trafficking, immune cell infiltrate, immune infiltration, intratumoral immune cell, tumor immune cell, Abscopal effect, abscopal activity, abscopal response, anti-PD-1, aPD-1, aPD1, anti programmed cell death 1, anti-PD1, anti-programmed cell death protein 1, antiPD-1, antiPD1, αPD-1, αPD1, side effect, draining lymph node, regional lymph node
