SynerGel: A Novel Tumor Microenvironment-Modulating Hydrogel for Local Immunotherapy

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PROJECT SUMMARY. Immunotherapy has become an emerging standard-of-care (SOC) for many different cancer types. However, only 15-20% of patients receive durable benefit. Other limitations include the toxicity of systemically-delivered immunomodulators which may require frequent, high doses and lead to immune-related adverse events (irAEs). The risk of severe, and potentially fatal, irAEs increases as the field moves towards immune/immune and immune/SOC combination therapies. As the “front line” of tumor/immune interaction, the tumor immune microenvironment (TIME) is a critical locus of immunomodulation, where the kinds of immunocytes in the TIME predict the likelihood of response to diverse immunotherapies. One strategy to favorably modulate the TIME is to localize multiple immunotherapeutics at the tumor through direct intratumoral delivery, reversing the immunosuppressive TIME while promoting anti-tumor effector cell immunity. This can enhance local concentration of drugs while minimizing systemic exposure and likelihood and severity of irAEs. The use of biomaterials as platforms for cancer immunotherapy provides the potential to intelligently direct and modulate immune cells in situ. Our drug-mimicking, peptide nanofiber hydrogel called “SynerGel” is at the forefront of this field, with the ability to deplete suppressive immune cells while simultaneously releasing diverse factors in a controlled manner within a specific volume. These multiple abilities allow for reduced off-target toxicity, dose- sparing, and targeting of multiple immune pathways to address the heterogeneous nature of cancers. The overall hypothesis of this proposal is that intratumoral injection of SynerGel renders immunologically refractory tumors sensitive to immune-mediated killing through multiple mechanisms including: 1) optimization of local effector/suppressor immunocyte ratios, 2) prolonged release of immune-stimulating agents, and 3) enhanced activation of recruited effector immunocytes. We propose to improve on the efficacy of our “first generation” MDP-based hydrogel system by designing a unique injectable, combinatorial immunotherapy platform based on the drug-mimicking next-generation MDP hydrogel called SynerGel in three aims: Aim 1 will evaluate SynerGel as an injectable, highly customizable cancer immunotherapy platform able to perform sustained delivery of multiple immunotherapeutics to the TIME. Aim 2 will explore the immunologic mechanisms contributing to SynerGel-mediated amelioration of the adverse HNSCC tumor microenvironment. Aim 3 will investigate the combination of SynerGel immunotherapy with standard-of-care radiotherapy (RT), looking to identify specific immune mechanisms induced by the combination of RT and immunomodulation, and allowing for effective therapy de-escalation by eliminating the need for chemotherapy, thus decreasing toxicity. By successfully accomplishing these aims, we hope to clarify the molecular/cellular mechanisms by which SynerGel can reverse resistance to both standard-of-care RT and immunomodulatory therapy in solid tumors and provide insights into how the adverse tumor microenvironment can be rendered more susceptible to immunotherapy.