Supramolecular Filament Hydrogel as a Universal Immunomodulator Carrier for Immunotherapy Combinations.

Abstract

A major challenge of cancer immunotherapy is to develop delivery strategies that can effectively and safely augment the immune system's antitumor response. Here, we report on the design and synthesis of a peptide-based supramolecular filament (SF) hydrogel as a universal carrier for localized delivery of three immunomodulating agents of distinct action mechanisms and different molecular weights, including an aPD1 antibody, an IL15 cytokine, and a STING agonist (CDA). We show that <i>in situ</i> hydrogelation can be triggered to occur upon intratumoral injection of SF solutions containing each of aPD1, IL15, or CDA. The formed hydrogel serves as a scaffold depot for sustained and MMP-2-responsive release of immunotherapeutic agents, achieving enhanced antitumor activities and reduced side effects. When administered in combination, the aPD1/IL15 or aPD1/CDA hydrogel led to substantially increased T-cell infiltration and prevented the development of adaptive immune resistance induced by IL15 or CDA alone. These immunotherapy combinations resulted in complete regression of established large GL-261 tumors in all mice and elicited a protective long-acting and systemic antitumor immunity to prevent tumor recurrence while eradicating distant tumors. We believe this SF hydrogel offers a simple yet generalizable strategy for local delivery of diverse immunomodulators for enhanced antitumoral response and improved treatment outcomes.