IL-1-based immunotherapy in HNSCC

基于免疫治疗的策略(即抗程序性细胞死亡蛋白-1(anti-PD1))是非常合适的 VA患者的选择与化疗策略相比具有更有利的毒性特征，并且 可被触发的显著持久的肿瘤反应。然而，只有少数患者从中受益。 在常规使用抗PD1药物之前，需要进行单剂免疫疗法和改进 一线治疗。因此，仍有必要确定新的替代免疫疗法 改善VA HNSCC患者生存结局的策略。我们认为白介素1(IL-1) 配体(如IL-1α和/或IL-1β)可能是一种有效的免疫治疗方法。IL-1信号转导 可通过增加树突状细胞(DC)的抗原提呈激活强大的抗肿瘤免疫反应， 触发自然杀伤(NK)细胞活性，以及CD4+和细胞毒CD8+T细胞的激活/增殖。 这表明，循环中IL-1配体水平的升高可能会触发抗肿瘤免疫并增强 HNSCC肿瘤对其他可诱导抗肿瘤反应的治疗策略的反应 放射治疗和抗PD1治疗。我们的初步数据显示，史无前例的持久T细胞-- 单次腹腔注射IL-1α聚酸酐的依赖性抗肿瘤反应 纳米粒(IL-1αNP)制剂以小鼠为单剂。此外，与管理 重组IL-1α引起严重的体重减轻和毒性，IL-1α纳米粒未显示明显的毒性迹象。 基于这一数据，我们认为使用纳米粒给药的IL-1α可能代表着一种很有前途的 其他被批准用于治疗触发HNSCC的药物的免疫治疗方法和佐剂 抗肿瘤免疫反应(如放射治疗和抗PD1)。我们假设IL-1NPs会触发 抗肿瘤免疫反应和增强HNSCC肿瘤对放射治疗和抗PD1治疗的反应。目标 1将评估IL-1NPs的治疗效果和安全性；Aim 2将检查IL-1NPs是否会增强 HNSCC肿瘤对放射治疗的反应；目标3将检查IL-1NPs是否会增强HNSCC肿瘤 对抗PD1免疫治疗的反应。如果成功，IL-1NP的交付将是一种有希望的 VA HNSCC患者的免疫治疗方法，我们希望这项工作将导致临床 包括IL-1NP注射在内的新的联合免疫治疗策略的评估。

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-1α and/or IL-1β) 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-1α polyanhydride nanoparticle (IL-1αNP) formulation to mice as a single agent. Additionally, in comparison to administration of recombinant IL-1α which elicited severe weight loss and toxicity, IL-1αNPs showed no obvious signs of toxicity. Based on this data we believe that IL-1α 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.