OVERCOMING TUMOR EVASION MECHANISMS IN HODGKIN DISEASE

克服霍奇金病的肿瘤逃避机制

• 批准号: 8182183
• 负责人: CLIONA M ROONEY
• 金额: $ 28.09万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8182183
• 关键词: Adenovirus Vector; Adoptive Immunotherapy; Adverse effects; Antigen Targeting; Antigens; Apoptosis; Autologous; Autologous Dendritic Cells; B-Lymphocytes; Biological Assay; Biopsy; Blood; Bulky Disease; Cell Culture Techniques; Cell Line; Cell Therapy; Cells; Clinical; Clinical Research; Coculture Techniques; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Distant Metastasis; Dominant Negative Receptor; Dominant-Negative Mutation; Dose; EBV-Specific Cytotoxic T-Lymphocyte; Effectiveness; Employee Strikes; Engineering; Environment; Firefly Luciferases; Flow Cytometry; Frequencies; Funding; Future; Galectin 1; Gene-Modified; Generations; Genes; Goals; Hodgkin Disease; Home environment; Human; Human Herpesvirus 4; Immune; Immune response; Immunocompetent; Immunohistochemistry; Immunotherapy; In Vitro; In complete remission; Infusion procedures; Interferons; Interleukin-10; Interleukin-12; Interleukin-13; Interleukin-2; Interleukin-4; Knockout Mice; LMP1; Leucocytic infiltrate; Life; Lymphocyte Function; Lymphoma; Malignant Neoplasms; Measures; Mediating; Modeling; Modification; Monitor; Monoclonal Antibodies; Mononuclear; Mus; Nasopharynx Carcinoma; Neuroblastoma; Non-Hodgkin' s Lymphoma; Outcome; Ovalbumin; Patients; Phase I Clinical Trials; Phenotype; Population; Primary Neoplasm; Principal Investigator; Production; Proteins; Protocols documentation; Radiation; Receptor Gene; Recruitment Activity; Recurrent disease; Reed-Sternberg Cells; Regulatory T-Lymphocyte; Relapse; Research Personnel; Resistance; Retroviral Vector; Safety; Schedule; Signal Transduction; Site; Solid Neoplasm; Specificity; T-Lymphocyte; TGFB1 gene; Testing; Th2 Cells; Time; Toxic effect; Transgenic Organisms; Tumor Antigens; Tumor-Infiltrating Lymphocytes; Vaccinated; Viral; Viral Antigens; Viral Proteins; anergy; arginase; biological adaptation to stress; cancer cell; cancer immunotherapy; cell type; chemokine; clinical efficacy; cytokine; granzyme B; human TGFBR2 protein; immunogenic; improved; in vivo; indoleamine; inhibitor/antagonist; interest; interleukin-12 receptor; lymph nodes; macrophage; melanoma; neoplastic cell; pre-clinical; programs; receptor; transduction efficiency; tumor; tumor growth; vector

The long-term goal of Project 1, led by C. Rooney, is to improve the outcome of immunotherapy for lymphomas associated with Epstein-Barr virus (EBV), especially Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL). Although studies during the previous funding cycle showed that cytotoxic T lymphocytes (CTLs) specific for the LMP2 protein of EBV home to tumor sites and produce antitumor effects (complete responses in 4 of 6 patients with relapsed disease), such therapy had clear shortcomings that would limit its effectiveness in future protocols for HD and NHL patients, and for other malignancies. Most prominent were the short-lived increases in the frequency and function of tumor-specific CTLs, particularly in patients with bulky disease. These observations suggested that optimal immune responses were being suppressed by the tumor microenvironment and by the tumor cells themselves, leading the investigators to propose (i) that LMP1- and LMP2-specific CTLs resistant to TGF-B, an immune inhibitory molecule produced by HD tumors, will have prolonged persistence and function in patients with relapsed disease, (ii) tumor antigen (TA)- specific CTLs expressing IL-12 will reverse the Th2 and negative immunoregulatory phenotype/function of tumor-infiltrating mononuclear cells, and (iii) TA-specific CTLs expressing IL-12 or constitutive T-bet, the master regulator of Tc1/Th1 functions and an inhibitor of GATA-3 , will have enhanced resistance to and efficacy against Th2 and Treg containing tumors. These predictions will be tested in three specific aims: to determine the safety and clinical efficacy of adoptively transferred LMP1- and LMP2-specific CTLs genetically modified to express a transdominant-negative TGF-beta type II receptor (DNR) in patients with EBV-positive HD or NHL (Aim 1); to evaluate the functional persistence of adoptively transferred DNR gene-modified EBV-CTLs in these patients (Aim 2); and to compare the safety and antitumor efficacy of TA-specific CTLs expressing IL-12 or T-bet in a model that mimics the regulatory environment of human HD. If the DNR, IL-12 or T-bet gene modifications of CTLs prove safe and enhance the survival and function of CTLs at tumor sites, this strategy could be introduced into the T-cell therapies evaluated in Projects 3 and 4. Lay summary - In many patients with Hodgkin disease and non-Hodgkin lymphoma, the cancer cells are infected with Epstein-Barr virus. The viral proteins in the lymphoma cells are attractive targets for immunotherapy. The investigators in this project are taking advantage of these viral targets by engineering a specific type of T cell to express proteins that should improve the ability of the modified cells to find and destroy EBV-positive tumors without producing toxic effects in the patient.

由C.鲁尼，是为了改善免疫治疗的结果， 与EB病毒（EBV）相关的淋巴瘤，特别是霍奇金病（HD）和非霍奇金淋巴瘤 淋巴瘤（NHL）。尽管上一个资助周期的研究表明，细胞毒性T淋巴细胞 特异性针对EBV的LMP 2蛋白的CTL归巢至肿瘤部位并产生抗肿瘤作用（完成 6例复发性疾病患者中有4例有反应），但这种疗法有明显的缺点， HD和NHL患者以及其他恶性肿瘤的未来方案的有效性。最突出的是 肿瘤特异性CTL的频率和功能的短暂增加，特别是在患有 巨大的疾病。这些观察结果表明，最佳免疫反应被抑制， 肿瘤微环境和肿瘤细胞本身，导致研究人员提出（i）， LMP 1和LMP 2特异性CTL对TGF-B（HD肿瘤产生的免疫抑制分子）具有抗性， 将在复发性疾病患者中具有延长的持久性和功能，（ii）肿瘤抗原（TA）- 表达IL-12的特异性CTL将逆转Th 2和负性免疫调节表型/功能， 肿瘤浸润单核细胞，和（iii）表达IL-12或组成型T-bet的TA特异性CTL， Tc 1/Th 1功能的主要调节剂和加塔-3的抑制剂，将具有增强的抵抗力， 针对含有Th 2和Treg的肿瘤的功效。这些预测将在三个具体目标中得到检验： 确定过继转移的LMP 1和LMP 2特异性CTL的安全性和临床疗效 经遗传修饰以在患有以下疾病的患者中表达反显性阴性TGF-β II型受体（DNR）： EBV阳性HD或NHL（目的1）;评估过继转移的DNR基因修饰的 这些患者中的EBV-CTL（目的2）;并比较TA特异性化疗的安全性和抗肿瘤疗效。 在模拟人HD调节环境的模型中表达IL-12或T-bet的CTL。如果 CTL的DNR、IL-12或T-bet基因修饰被证明是安全的，并增强了CTL的存活和功能。 在肿瘤部位的CTL，该策略可以引入到项目3和4中评价的T细胞疗法中。 在许多霍奇金病和非霍奇金淋巴瘤患者中，癌细胞是 感染了EB病毒淋巴瘤细胞中的病毒蛋白质是免疫治疗的有吸引力的靶点。 免疫疗法。该项目的研究人员正在利用这些病毒靶点， 特定类型的T细胞表达蛋白质，这些蛋白质应该提高修饰细胞发现和 破坏EBV阳性肿瘤而不对患者产生毒性作用。