Depleting exosomes to improve responses to immune therapy in HNSCC

消耗外泌体以改善 HNSCC 免疫治疗的反应

• 批准号: 10027563
• 负责人: Annette Marleau
• 金额: $ 62.7万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10027563
• 关键词: Antibodies; Antitumor Response; Blood; Blood Circulation; Cancer Patient; Cell Therapy; Cells; Characteristics; Clinical; Clinical Data; Collaborations; Data; Development; Device Removal; Devices; Dialysis procedure; Disease; Disease Progression; Effector Cell; Excision; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human Papillomavirus; Immune; Immune Tolerance; Immune checkpoint inhibitor; Immunocompetence; Immunocompetent; Immunologic Markers; Immunosuppression; Immunotherapy; Impairment; Institution; Ligands; Malignant Neoplasms; Medical; Metastatic/Recurrent; MicroRNAs; Minority; Molecular Profiling; Monitor; Monoclonal Antibodies; Oncogenes; Operative Surgical Procedures; Patients; Phase; Phase II Clinical Trials; Plasma; Play; Proteins; Recovery; Recurrence; Rejuvenation; Reporting; Research; Role; Safety; Sampling; Site; Survival Rate; Testing; Therapeutic; Therapy trial; Tumor Immunity; Tumor-Derived; United States Food and Drug Administration; Unresectable; Virus; arm; base; carcinogenesis; chemoradiation; design; exosome; follow-up; immune function; immunosuppressed; improved; improved outcome; mouse model; novel therapeutics; outcome forecast; preclinical study; predictive tools; programmed cell death ligand 1; programmed cell death protein 1; programs; relapse prediction; response; restoration; tumor; tumor ablation; tumor growth

PROJECT SUMMARY/ABSTRACT Patients with head and neck squamous cell cancer (HNSCC) continue to have poor prognosis, largely because of disease recurrence and/or the development of metastatic disease. New therapies are an unmet need for patients with recurrent/metastatic HNSCC. Immune-based therapies, including immune checkpoint inhibitors (ICIs), have been introduced and Pembrolizumab, an anti-PD-1 monoclonal antibody, is currently approved by the US Food and Drug Administration (FDA) for the first-line treatment of patients with unresectable recurrent/metastatic HNSCC. Use of ICIs is based on the premise that rejuvenation of suppressed anti-tumor immunity in cancer patients will improve outcome. Unfortunately, only a minority of the HNSCC patients treated with ICIs responds to the immunotherapy (IT), possibly due to the unresponsiveness of immune cells to activation in profoundly immunosuppressed HNSCC patients. Exosomes have emerged as major contributors to tumor- associated immune suppression and a significant barrier to antibody-based and adoptive cell-based therapies in cancer. We have reported that IT is not effective in cancer patients with high levels of circulating exosomes, and have also shown that circulating exosomes carrying immunosuppressive ligands, such as PD-L1, impair functions of immune effector cells in HNSCC patients and negatively impact disease progression. Therefore, we hypothesize that the removal of immunosuppressive exosomes from the circulation of HNSCC patients prior to IT will promote immune cell recovery and significantly increase the response rate. To test this hypothesis and develop novel therapeutic capabilities for cancer patients, we have established a partnership between Aethlon Medical, Inc. and three academic institutions. Aethlon Medical, Inc. has developed the Hemopurifier®, a good manufacturing practices (GMP)-compatible device for removal of blood-borne viruses and exosomes and designed for use with standard dialysis machines. In Aim 1, we will characterize exosomes removed from HNSCC patients’ plasma by the research-grade version of the Hemopurifier. We will correlate the immunosuppressive profiles, functions and miRNA content of these exosomes with clinicopathological endpoints and disease activity. In addition, using a mouse model, we will demonstrate that depletion of exosomes restores anti-tumor immunity and inhibits tumor growth, while delivery of suppressive exosomes promotes tumor growth and carcinogenesis. In Aim 2, we will conduct a single-arm Phase II clinical trial using a clinical-grade Hemopurifier to establish that removal of exosomes from the circulation of patients with recurrent/metastatic HNSCC improves responses to IT. Finally, in Aim 3, we will utilize data and samples from the Phase II clinical trial to identify predictors of benefit from exosome depletion by Hemopurifier prior to IT. Successful completion of the proposed project is expected to result in novel therapeutic capabilities and new predictive tools based on plasma exosomes to improve clinical responses to ITs for patients with HNSCC.

项目总结/摘要 头颈部鳞状细胞癌（HNSCC）患者的预后仍然很差，这主要是因为 疾病复发和/或转移性疾病的发展。新疗法是一种未满足的需求， 复发性/转移性HNSCC患者。基于免疫的疗法，包括免疫检查点抑制剂 （ICI），并且Pembrolizumab，一种抗PD-1单克隆抗体，目前已被批准用于治疗PD-1。 美国食品和药物管理局（FDA）用于不可切除的患者的一线治疗 复发性/转移性HNSCC。ICIs的使用是基于这样的前提，即抑制的抗肿瘤药物的年轻化 癌症患者的免疫力将改善结果。不幸的是，只有少数HNSCC患者接受治疗， ICIs对免疫疗法（IT）有反应，可能是由于免疫细胞对激活无反应性 在严重免疫抑制的HNSCC患者中外来体已经成为肿瘤的主要贡献者- 相关的免疫抑制和基于抗体和基于过继细胞的治疗的显著障碍 在癌症中。我们已经报道了IT对具有高水平循环外泌体的癌症患者无效， 并且还表明，携带免疫抑制配体（如PD-L1）的循环外泌体损害了 HNSCC患者的免疫效应细胞的功能，并对疾病进展产生负面影响。所以我们 假设免疫抑制性外泌体从HNSCC患者的循环中去除， 它将促进免疫细胞的恢复，并显着提高反应率。为了验证这一假设， 为癌症患者开发新的治疗能力，我们与Aethlon建立了合作伙伴关系， 医疗用品有限公司三个学术机构。Aethlon Medical，Inc.开发了Hemopurifier®，一种良好的 生产规范（GMP）兼容装置，用于清除血液传播病毒和外来体， 设计用于标准透析机。在目标1中，我们将表征从 HNSCC患者的血浆通过研究级版本的血液净化器。我们将把 这些外泌体的免疫抑制特性、功能和miRNA含量与临床病理学终点 和疾病活动。此外，使用小鼠模型，我们将证明外泌体的消耗恢复了 抗肿瘤免疫和抑制肿瘤生长，而抑制性外泌体的递送促进肿瘤生长 和致癌作用。在目标2中，我们将进行一项单组II期临床试验， 血液净化器用于确定从复发性/转移性肿瘤患者的循环中清除外来体 最后，在目标3中，我们将利用来自II期临床试验的数据和样本， 确定IT前通过血液净化器去除外泌体获益的预测因素的试验。成功完成 预计该项目将产生新的治疗能力和基于 血浆外泌体以改善HNSCC患者对IT的临床应答。