Reversal of CMV-specific Immune Deficits in Patients with Glioblastoma

胶质母细胞瘤患者 CMV 特异性免疫缺陷的逆转

• 批准号: 8721684
• 负责人: DUANE A. MITCHELL
• 金额: $ 30.82万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721684
• 关键词: Affect; Antigens; Autoimmune Process; Brain; Cell physiology; Cells; Chronic; Clinical; Clinical Trials; Coupled; Cytomegalovirus; Cytoplasmic Granules; Data; Dendritic Cells; Diagnosis; Disease; Dose-Limiting; Effector Cell; Excision; Failure; Frequencies; Gene-Modified; Generations; Glioblastoma; Goals; Granzyme; HIV; Human; IL2RA gene; Immune; Immune response; Immune system; Immunity; Immunologics; Immunosuppressive Agents; Immunotherapy; In Vitro; Inflammatory; Integumentary system; Interferons; Interleukin-15; Interleukin-2; Interleukin-7; Laboratories; Lymphocyte; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Methods; Mus; Nature; Newly Diagnosed; Operative Surgical Procedures; Outcome; Patients; Peptides; Phase; Physiologic pulse; Primates; Production; Proteins; Public Health; Quality of life; RNA; Radiation; Regulatory T-Lymphocyte; Research; Risk; SIV; Safety; Staphylococcal Enterotoxin B; Supplementation; Surveys; System; T cell response; T-Lymphocyte; TNF gene; Toxic effect; Tumor Antigens; Vaccination; Vaccines; Viral; Viral Proteins; Virus Diseases; aggressive therapy; arm; cancer therapy; chemotherapy; cytokine; immunogenic; improved; in vivo; infectious disease model; killings; neoplastic cell; novel; pathogen; response; restoration; targeted delivery; treatment strategy; tumor

The recent discovery and confirmation by four independent laboratories, including ours, that malignant gliomas are frequently associated with expression of human cytomegalovirus antigens provides a unique opportunity to harness the cytolytic power of the immune system to eradicate CMV-infected tumor cells without harming surrounding normal brain. Our efforts in enhancing CMV-specific immune responses using CMV pp65 RNA- pulsed dendritic cells (DCs) have demonstrated the capacity to enhance CMV-specific cellular and humoral responses and elicit promising radiographic and clinical responses in patients with newly-diagnosed GBM. Despite these encouraging results, we have found that patients with GBM elicit profound immunologic CMV- specific deficts at diagnosis that are characterized by the inability to mount effective polyfunctional T cell responses (simultaneous production of IL-2, IFN, TNF, and cytolytic granules (CD107)) upon stimulation with CMV antigens in vitro. Polyfunctional T cell responses have been shown to mediate the effective control of chronic viral infections such as HIV and CMV in humans, and while DC vaccination improved the frequency of monofunctional CMV-specific T cells, polyfunctional responses were not enhanced. Importantly, we have found that polyfunctional CMV-specific T cell responses could be restored in these same patients in vitro using pp65 RNA pulsed DCs coupled with addition of exogenous IL-2 or through the removal of CD4+CD25+FOXP3+ regulatory T cells (Tregs) prior to stimulation. The results suggest that reversal of cell-mediated deficits in vivo in patients with GBM may be a feasible goal and may significantly improve the efficacy of antitumor immunotherapy. In this proposal, we will explore methods to reverse cell-mediated deficits in patients with GBM using CMV RNA pulsed DCs co-transfected with RNAs encoding for cytokines that favorably modulate polyfunctional T cell responses and inhibit expansion of immunosuppressive Tregs. The use of RNA-modified DCs may allow for the targeted delivery of immunomodulatory cytokines without the induction of systemic toxicity or autoimmune risks of systemic Treg inhibition. These studies have significant potential to improve clinical outcomes for patients with GBM.

包括我们在内的四个独立实验室最近的发现和证实，恶性胶质瘤 经常与人类巨细胞病毒抗原的表达相关提供了独特的机会 利用免疫系统的细胞溶解能力在不伤害的情况下根除CMV感染的肿瘤细胞 周围正常的大脑。我们利用CMV pp65 RNA增强CMV特异性免疫反应的努力- 脉冲树突状细胞(DC)已显示出增强CMV特异性细胞和体液的能力 对新诊断的GBM患者的反应和有希望的放射学和临床反应。 尽管有这些令人鼓舞的结果，但我们发现，患有GBM的患者会引发深刻的免疫CMV- 诊断时的特殊缺陷，其特征是不能安装有效的多功能T细胞 对刺激的反应(同时产生IL-2、干扰素、肿瘤坏死因子和细胞溶解颗粒(CD107)) CMV抗原的体外实验。多功能T细胞反应已被证明介导有效控制 人类的慢性病毒感染，如艾滋病毒和巨细胞病毒，虽然DC疫苗接种增加了 单功能CMV特异性T细胞、多功能应答未见增强。重要的是，我们发现 在体外使用pp65可以在这些患者中恢复多功能CMV特异性T细胞反应 外源性IL-2或通过去除CD4+CD25+FOXP3+联合RNA冲击DC 刺激前的调节性T细胞(Tregs)。结果表明，体内细胞介导的缺陷的逆转 在患有GBM的患者中可能是一个可行的目标，并可能显著提高抗肿瘤的疗效 免疫疗法。在这项建议中，我们将探索逆转细胞介导的缺陷的方法 利用CMV RNA冲击的树突状细胞与编码有利调节细胞因子的RNA共转染的GBM 多功能T细胞反应和抑制免疫抑制树突状细胞的扩张。RNA修饰技术的应用 DC可能允许靶向传递免疫调节细胞因子而不诱导全身性 全身Treg抑制的毒性或自身免疫风险。这些研究有很大的改进潜力。 GBM患者的临床转归。