OVERCOMING TUMOR EVASION MECHANISMS IN HODGKIN DISEASE

克服霍奇金病的肿瘤逃避机制

基本信息

批准号：
7407152
负责人：
CLIONA M ROONEY
金额：
$ 26.81万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7407152
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 Line 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 End Point Engineering Environment Firefly Luciferases Flow Cytometry Frequencies Funding Future Galactose Binding Lectin Gene-Modified Generations Genes Goals Hodgkin Disease Home environment Human Human Herpesvirus 4 Immune Immune response Immunocompetent 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&apos s Lymphoma Outcome Ovalbumin Patients Phase I Clinical Trials Phenotype Polymerase Chain Reaction Population Primary Neoplasm Principal Investigator Production Proteins Protocols documentation Radiation Range Receptor Gene Recruitment Activity Recurrent disease Reed-Sternberg Cells Relapse Research Personnel Resistance Retroviral Vector Safety Schedule Signal Transduction Site Solid Neoplasm Specificity T-Lymphocyte Testing Th2 Cells Time Toxic effect 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 concept cytokine cytotoxic 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

项目摘要

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 ymphoma (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-p, 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 genemodified EBV-CTLs in these patients (Aim 2); and to compare the safety and antitumor efficacy of TAspecific 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. Rooney 领导的项目 1 的长期目标是改善免疫治疗的结果与 Epstein-Barr 病毒 (EBV) 相关的淋巴瘤，尤其是霍奇金病 (HD) 和非霍奇金病淋巴瘤（NHL）。尽管上一个资助周期的研究表明细胞毒性 T 淋巴细胞 (CTL) 特异性针对 EBV 的 LMP2 蛋白，定位于肿瘤位点并产生抗肿瘤作用（完整 6 名复发性疾病患者中的 4 名有反应），这种疗法有明显的缺点，会限制其疗效未来方案对 HD 和 NHL 患者以及其他恶性肿瘤的有效性。最突出的是肿瘤特异性 CTL 的频率和功能的短暂增加，特别是在患有以下疾病的患者中体积大的疾病。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） LMP1 和 LMP2 特异性 CTL 对 TGF-β（HD 肿瘤产生的一种免疫抑制分子）具有抗性，在疾病复发的患者中将具有长期的持久性和功能，（ii）肿瘤抗原（TA）- 表达 IL-12 的特定 CTL 将逆转 Th2 和阴性免疫调节表型/功能肿瘤浸润单核细胞，以及 (iii) 表达 IL-12 或组成型 T-bet 的 TA 特异性 CTL， Tc1/Th1 功能的主要调节剂和 GATA-3 的抑制剂，将具有增强的抵抗力和对含有 Th2 和 Treg 的肿瘤具有功效。这些预测将在三个具体目标上进行测试：确定过继转移的 LMP1 和 LMP2 特异性 CTL 的安全性和临床疗效经过基因改造，在患有以下疾病的患者中表达转显性阴性 TGF-β II 型受体 (DNR) EBV 阳性 HD 或 NHL（目标 1）；评估过继转移的 DNR 基因修饰的功能持久性这些患者中的 EBV-CTL（目标 2）；并比较 TAspecific 的安全性和抗肿瘤功效在模拟人类 HD 监管环境的模型中表达 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，并增强了细胞的存活和功能肿瘤部位的 CTL，该策略可以引入到项目 3 和 4 中评估的 T 细胞疗法中。简单总结 - 在许多患有霍奇金病和非霍奇金淋巴瘤的患者中，癌细胞是感染了 Epstein-Barr 病毒。淋巴瘤细胞中的病毒蛋白是有吸引力的靶标免疫疗法。该项目的研究人员正在利用这些病毒目标，设计一个特定类型的 T 细胞表达蛋白质，这些蛋白质应提高修饰细胞发现和消灭 EBV 阳性肿瘤而不会对患者产生毒性作用。