Development of a tumor-retentive immunostimulant as adjunct therapy for solid tumor cancers

PROJECT SUMMARY/ABSTRACT 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 preliminary studies 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-001 will improve efficacy of standard treatment (e.g., checkpoint inhibitors) with minimal side effects, leading to improved outcomes and survival.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.