An injectable hydrogel enhances intratumoral retention and antitumor efficacy of cytokine immunotherapy in murine triple negative breast tumor models

Abstract

Systemic delivery of immunotherapy is dose-limited and often causes serious immune-related adverse events . Intratumoral injections can reduce systemic immunotoxicities and increase immunotherapy concentrations within a tumor. However, high pressures associated with direct tumor injection limits injectate retention, as low viscosity, saline-based solutions rapidly leak out of tumors. Viscoelastic solids, such as hydrogels, can improve local retention of co-formulated immunotherapies and provide sustained delivery. Here, we investigated the potential of a novel injectable hydrogel, called XCSgel, to localize immunotherapies within murine models of orthotopic triple-negative breast cancer (TNBC). Ex vivo and in vivo fluorescence imaging revealed enhanced intratumoral retention of immunotherapies co-formulated in XCSgel. Initial antitumor studies evaluated a range of antitumor cytokines co-formulated with XCSgel. Subsequent antitumor and rechallenge studies focused on the promising co-formulation of interleukin-12 (IL-12) and XCSgel (XCSgel-IL12). A single injection of XCSgel-IL12 eliminated 86 % of E0771 and 20 % of mWnt orthotopic primary TNBC tumors. Mice rendered tumor-free resisted a live tumor challenge. XCSgel-IL12 also eliminated untreated abscopal E0771 tumors in 67 % of mice. XCSgel-IL12 induced profound changes to the tumor-immune microenvironment, including a 3-fold reduction in the frequency of exhausted CD8 + T cells and a 3.2-fold increase in activated, proliferating CD8 + T cells. XCSgel and XCSgel-IL12 were well tolerated with no severe local or systemic side effects . Overall, XCSgel-IL12 is a promising localized immunotherapy capable of safely eliminating both primary treated and secondary abscopal tumors, indicating that systemic immunotherapy may not be required for systemic control of cancer.

Topics & Concepts