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: 10640915
• 负责人: Theresa L. Whiteside
• 金额: $ 71.82万
• 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/10640915
• 关键词: Antibodies; Antitumor Response; Blood; Cancer Patient; Cell Therapy; Cells; Characteristics; Circulation; Clinical; Clinical Data; Collaborations; Combined Modality Therapy; Data; Development; Device Removal; Devices; Dialysis procedure; Disease; Disease Progression; Effector Cell; Excision; Goals; Good Manufacturing Process; 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; Prognosis; Proteins; Recovery; Recurrence; Recurrent disease; Rejuvenation; Reporting; Research; Role; Safety; Sampling; Site; Survival Rate; Testing; Therapeutic; Therapy trial; Tumor Immunity; Tumor Promotion; Tumor-Derived; United States Food and Drug Administration; Unresectable; Virus; arm; carcinogenesis; chemoradiation; design; exosome; follow-up; immune function; immunosuppressed; improved; improved outcome; mouse model; novel therapeutics; pembrolizumab; 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.

项目摘要/摘要 头颈部鳞状细胞癌(HNSCC)患者的预后仍然很差，主要是因为 疾病复发和/或转移性疾病的发展。新疗法是一种未得到满足的治疗需求 复发/转移性HNSCC患者。基于免疫的治疗，包括免疫检查点抑制剂 (ICIS)，pembrolizumab，一种抗PD-1的单抗目前正被批准 美国食品和药物管理局(FDA)为无法手术切除的患者提供一线治疗 复发/转移性HNSCC。使用ICIS是基于这样一个前提，即年轻化抑制的抗肿瘤 癌症患者的免疫力将改善预后。不幸的是，只有少数HNSCC患者接受了治疗 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 在免疫深度抑制的HNSCC患者中。外显体已经成为肿瘤的主要贡献者- 相关免疫抑制和抗体和过继细胞治疗的重大障碍 在癌症中。我们已经报道过，它对循环外切体水平高的癌症患者无效， 研究还表明，携带免疫抑制配体的循环外切体，如PD-L1，会损害 免疫效应细胞在HNSCC患者中的功能和对疾病进展的负面影响。因此，我们 假设在HNSCC患者的循环中去除免疫抑制外体之前 它将促进免疫细胞的恢复，显著提高应答率。为了检验这一假说， 为癌症患者开发新的治疗能力，我们与爱思强公司建立了合作伙伴关系 医疗公司和三个学术机构。Aethlon Medical，Inc.开发了血液净化器®，这是一种很好的 符合生产规范(GMP)的血液传播病毒和外切体清除设备以及 专为使用标准透析机而设计。在目标1中，我们将描述从 HNSCC患者的血浆由研究级版本的血液净化器提供。我们将关联 这些具有临床病理终点的外切体的免疫抑制谱、功能和miRNA含量 和疾病活跃度。此外，使用小鼠模型，我们将演示外切体的耗尽恢复 抗肿瘤免疫和抑制肿瘤生长，而抑制外切体的传递促进肿瘤生长 和致癌作用。在目标2中，我们将使用临床级进行单臂II期临床试验 血液净化器用于建立从复发/转移患者的循环中去除外切体的方法 HNSCC改进了对IT的响应。最后，在目标3中，我们将利用来自第二阶段临床的数据和样本 试验以确定IT前血液净化器消耗外切体的益处的预测因素。成功完成 预计将产生新的治疗能力和新的预测工具，基于 血浆外切体以改善HNSCC患者对ITS的临床反应。

项目成果

Small EV in plasma of triple negative breast cancer patients induce intrinsic apoptosis in activated T cells.

• DOI: 10.1038/s42003-023-05169-3
• 发表时间: 2023-08-04
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Mondal, Sujan Kumar;Haas, Derick;Han, Jie;Whiteside, Theresa L. L.
• 通讯作者: Whiteside, Theresa L. L.

Characteristics of Exosomes and the Vascular Landscape Regulate Exosome Sequestration by Peripheral Tissues and Brain.

• DOI: 10.3390/ijms232012513
• 发表时间: 2022-10-19
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Proteomic profiles of melanoma cell-derived exosomes in plasma: discovery of potential biomarkers of melanoma progression.

• DOI: 10.1097/cmr.0000000000000762
• 发表时间: 2021-10-01
• 期刊: Melanoma research
• 影响因子: 2.2
• 作者: Mondal SK;Whiteside TL
• 通讯作者: Whiteside TL

The Role of Tumor-Derived Exosomes (TEX) in Shaping Anti-Tumor Immune Competence.

• DOI: 10.3390/cells10113054
• 发表时间: 2021-11-06
• 期刊: Cells
• 影响因子: 6
• 作者: Whiteside TL

Immunosuppressive functions of melanoma cell-derived exosomes in plasma of melanoma patients.

• DOI: 10.3389/fcell.2022.1080925
• 发表时间: 2022
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5