IL-1-based immunotherapy in HNSCC

HNSCC 基于 IL-1 的免疫疗法

• 批准号: 10553171
• 负责人: Andrean Llewela Burnett
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553171
• 关键词: Address; Adjuvant; Age; Antigen Presentation; Antitumor Response; Biodistribution; Body Weight decreased; Cancer Patient; Clinical Trials; Combination immunotherapy; Data; Dendritic Cells; Disease; Dose; Dose Limiting; Drug Kinetics; Encapsulated; Formulation; Fractionation; Goals; HPV-negative head and neck cancer; Head and Neck Squamous Cell Carcinoma; Hexanes; Human Papillomavirus; Hypotension; Immune; Immune response; Immunotherapeutic agent; Immunotherapy; Inbred BALB C Mice; Inflammatory; Intention; Interleukin-1; Interleukin-1 alpha; Interleukin-1 beta; Kinetics; Ligands; Mediating; Minority; Mus; Natural Killer Cells; Patients; Polyanhydrides; Proliferating; Property; Protocols documentation; Radiation therapy; Recombinant Interleukin-1; Recombinants; Recurrence; Safety; Signal Transduction; Surface; Symptoms; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Tumor Immunity; Up-Regulation; Veterans; Work; anti-PD-1; anti-PD1 therapy; anti-tumor immune response; cardiovascular effects; chemotherapy; comorbidity; controlled release; copolymer; curative treatments; cytokine; cytotoxic CD8 T cells; high risk; improved; intraperitoneal; lifestyle factors; mouse model; nanoparticle; nanoparticle delivery; novel; palliation; research clinical testing; response; side effect; survival outcome; tumor

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.

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递送的IL-1α给药可能是一种有前途的 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。

项目成果

Prognostic Role of Combined EGFR and Tumor-Infiltrating Lymphocytes in Oral Squamous Cell Carcinoma.

• DOI: 10.3389/fonc.2022.885236
• 发表时间: 2022
• 期刊: FRONTIERS IN ONCOLOGY
• 影响因子: 4.7
• 作者: Wongpattaraworakul, Wattawan;Gibson-Corley, Katherine N.;Choi, Allen;Buchakjian, Marisa R.;Lanzel, Emily A.;Rajan, K. D. Anand;Simons, Andrean L.
• 通讯作者: Simons, Andrean L.