Development of Localized Triple-Negative Breast Cancer Immunotherapy

ABSTRACT Immunotherapy has revolutionized the way cancer is treated. However, limitations in efficacy combined with immune-related toxicities following systemic administration of immunotherapy motivate the development of safer, more effective approaches. Interest in intratumoral delivery of immunotherapeutics has increased in recent years. Intratumoral or intralesional injections have the potential to maximize the delivery of immunotherapies within the tumor while alleviating toxicities associated with traditional systemic delivery of broadly activating immunotherapies. Unfortunately, the feasibility and efficiency of intratumoral injections are grossly overestimated. Even with image-guidance, intratumoral injections often miss a targeted tumor and/or injected contents quickly leak out of a tumor due to high hydrostatic pressures. Viscoelastic hydrogels can resist shear forces that typically expel saline-based solutions from tumors after an injection. Formulating immunotherapeutics within hydrogels, therefore, may improve retention and overall exposure to immunotherapy within an injected lesion. Our preliminary and published data demonstrate that a novel injectable, imageable, biocompatible hydrogel, called XCSgel, can increase the retention of co-formulated immunotherapies leading to profound increases in antitumor activity. Specifically, interleukin-12 (IL-12) formulated in XCSgel (XCSgel-IL12) is retained within an injected tumor for up to 4 weeks and can safely eliminate the majority of injected and uninjected distal breast tumors. XCSgel is tunable through manipulation of several parameters, leading to multiple variations with different mechanical properties, degradation rates, release kinetics, etc. It is not obvious which type of XCSgel would maximize the antitumor potential of IL-12. Thus, it is important to optimize XCSgel-IL-12 prior to clinical translation. The overarching goal of this proposed Phase I STTR project is to identify and de-risk a lead XCSgel- IL12 candidate with demonstrated efficacy and safety profiles in stringent murine TNBC models. Aim 1 will focus on synthesizing, characterizing, and optimizing XCSgel-IL12 in a rigorous downselect process from twelve potential candidates to three. Aim 2 will evaluate the pharmacokinetics/pharmacodynamics, safety and toxicology of the top three XCSgel-IL12 candidates. Although localized XCSgel-IL12 immunotherapy may be effective in controlling a range of solid malignancies, this project will focus on triple-negative breast cancer (TNBC) as an initial indication. TNBC is an aggressive subtype of breast cancer that requires debilitating and toxic treatments and yet suffers from unacceptably high recurrence rates.