Immunotherapy-based strategies (i.e. anti-programmed cell death protein-1 (anti-PD1) are highly suitable options for VA patients given the more favorable toxicity profile compared to chemotherapy strategies and the remarkable durable tumor responses that can be triggered. However, only a minority of patients derive benefit from single-agent immunotherapies and improvements are needed before routine use of anti-PD1 agents as first-line treatment. Therefore there remains a significant need to identify novel alternative immunotherapeutic strategies in order to improve survival outcomes for VA HNSCC patients. We propose that interleukin-1 (IL-1) ligands (e.g. IL-1? and/or IL-1?) may represent an effective immunotherapy in HNSCC patients. IL-1 signaling can activate a robust anti-tumor immune response via increased antigen presentation by dendritic cells (DCs), triggering of natural killer (NK) cell activity, and activation/proliferation of CD4+ and cytotoxic CD8+ T cells. This suggests that increasing levels of circulating IL-1 ligands may trigger anti-tumor immunity and enhance HNSCC tumor response to other therapeutic strategies that can induce anti-tumor responses such as radiotherapy and anti-PD1 therapy. Our preliminary data has shown unprecedented and durable T cell- dependent anti-tumor responses with a single intraperitoneal administration of an IL-1? polyanhydride nanoparticle (IL-1?NP) formulation to mice as a single agent. Additionally, in comparison to administration of recombinant IL-1? which elicited severe weight loss and toxicity, IL-1?NPs showed no obvious signs of toxicity. Based on this data we believe that IL-1? administration using nanoparticle delivery may represent a promising immunotherapeutic approach AND adjuvant to other agents approved for the treatment of HNSCC that trigger anti-tumor immune responses (e.g. radiotherapy and anti-PD1). We hypothesize that IL-1NPs will trigger an anti-tumor immune response and enhance HNSCC tumor response to radiotherapy and anti-PD1 therapy.
Aim 1 will evaluate the therapeutic efficacy and safety profile of IL-1NPs;
Aim 2 will examine if IL-1NPs will enhance HNSCC tumor response to radiotherapy;
and Aim 3 will examine if IL-1NPs will enhance HNSCC tumor response to anti-PD1 immunotherapy. If successful, IL-1NP delivery would represent a promising immunotherapeutic approach for VA HNSCC patients and we are hopeful that this work will lead to the clinical evaluation of novel combination immunotherapy strategies that include IL-1NP delivery.
Veterans are at a high risk for developing HNSCC due to certain lifestyle factors and existing co-morbidities due to age compared to non-Veterans. Because of the high co-morbidity seen in VA patients, conventional chemotherapy is not appropriate for many VA patients. However, immunotherapy-based strategies are highly suitable options for VA patients given the more favorable toxicity profile compared to other chemotherapy strategies and the remarkable durable responses that can be triggered. Therefore, it is of extreme importance to continue to investigate novel immunotherapeutic strategies in order to improve durable response rates in VA HNSCC patients. The current proposal tests if IL-1NPs will trigger an anti-tumor immune response and enhance HNSCC tumor response to radiotherapy and anti-PD1 therapy. If successful, IL-1NP delivery would represent a promising immunotherapeutic approach for VA HNSCC patients and we are hopeful that this work will lead to the clinical evaluation of novel combination immunotherapy strategies that include IL-1NP delivery.
