Cytokines coordinate essential mechanisms required for an antitumor response. As a result, they robustly synergize with other immunotherapies. Unfortunately, the clinical use and approval of cytokines is frequently plagued by dose-limiting toxicities. Improving the therapeutic index of cytokines can be achieved by better localizing their effects to the tumor and away from healthy tissue. Recent efforts have shown that local injections of immunomodulatory agents at or around a tumor lesion improve the efficacy and reduce the systemic exposure of these agents. However, even when administered directly into a tumor, cytokines exhibit rapid tumor clearance and limited intratumoral retention, thus doing little to address issues of toxicity and efficacy. Here we demonstrate that extracellular matrix (ECM) anchoring of intratumorally administered cytokines is a facile strategy to retain and confine these agents in the tumor. Although the ECM is an abundant component of both tumors and healthy tissue alike, intratumoral administration obviates the need to target a tumor-specific antigen. Instead, the abundance of matrix lends itself to being an effective and general target for localization across all solid tumors. ECM-anchoring of cytokines via fusion to a matrix-binding protein significantly improves their therapeutic index. Additionally, the combination of ECM-anchored cytokines with a systemic immunotherapy (e.g., a tumor-targeting antibody, checkpoint blockade, a cancer vaccine, or CAR-T-cell therapy) enhances overall survival in syngeneic tumor models compared to combination treatments using unanchored cytokines. Cytokines that are actively retained in the tumor can safely and significantly potentiate systemic immunotherapy. Given the abundant expression of ECM across different cancers, matrix-anchoring of cytokines embodies a tumor-agnostic strategy that can readily be combined with other immunotherapeutic modalities.
Citation Format: Noor Momin. Extracellular matrix anchoring of locally administered cytokines safely potentiates systemic cancer immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A206.