IL-1-based immunotherapy in HNSCC

基于免疫疗法的策略（即抗程序性细胞死亡蛋白-1（抗PD 1））非常适合 考虑到与化疗策略相比更有利的毒性特征， 可以触发的显著持久的肿瘤反应。然而，只有少数患者受益 在常规使用抗PD 1药物之前， 一线治疗因此，仍然非常需要鉴定新的替代免疫调节剂。 策略，以改善VA HNSCC患者的生存结局。我们认为白细胞介素-1（IL-1） 在HNSCC患者中，IL-1α和/或IL-1β配体可能是一种有效的免疫疗法。IL-1信号转导 可以通过增加树突状细胞（DC）的抗原呈递来激活强有力的抗肿瘤免疫应答， 触发自然杀伤（NK）细胞活性，以及CD 4+和细胞毒性CD 8 + T细胞的活化/增殖。 这表明循环IL-1配体水平的增加可能引发抗肿瘤免疫并增强肿瘤细胞的免疫应答。 HNSCC肿瘤对其他可诱导抗肿瘤反应的治疗策略的反应，例如 放疗和抗PD 1治疗。我们的初步数据显示前所未有的持久的T细胞- IL-1α聚酐单次腹腔内给药的依赖性抗肿瘤反应 在一个实施方案中，将IL-1αNP纳米颗粒制剂作为单一药剂给予小鼠。此外，与施用 重组IL-1α引起严重的体重减轻和毒性，IL-1αNPs没有显示出明显的毒性迹象。 基于这些数据，我们认为使用纳米颗粒递送的IL-1α给药可能代表了一种有前途的方法， 免疫方法和佐剂的其他药物批准用于治疗HNSCC，触发 抗肿瘤免疫应答（例如放疗和抗PD 1）。我们假设IL-1 NPs会触发 抗肿瘤免疫应答并增强HNSCC肿瘤对放疗和抗PD 1治疗的应答。目的 目的1将评估IL-1 NPs的治疗效果和安全性;目的2将检查IL-1 NPs是否会增强 HNSCC肿瘤对放射治疗的反应;目标3将检查IL-1 NPs是否会增强HNSCC肿瘤 抗PD 1免疫治疗的反应。如果成功，IL-1 NP递送将代表一种有希望的 我们希望这项工作将导致VA HNSCC患者的临床 评估包括IL-1 NP递送的新型联合免疫治疗策略。

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.