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：
8217340
负责人：
CLIONA M ROONEY
金额：
$ 27.18万
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
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8217340
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 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 Guanosine Triphosphate 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&apos s Lymphoma Outcome Ovalbumin Patients Phase I Clinical Trials Phenotype Population Primary Neoplasm Principal Investigator Production Proteins Protocols documentation Radiation 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 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 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. Rooney领导的项目1的长期目标是改善免疫疗法的结果与爱泼斯坦 - 巴尔病毒（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）。尽管上一个资金周期的研究表明细胞毒性T淋巴细胞（CTL）特有的EBV房屋的LMP2蛋白针对肿瘤部位并产生抗肿瘤作用（完整在6例复发性疾病患者中有4例的反应）这种疗法存在明显的缺点，这将限制对HD和NHL患者以及其他恶性肿瘤的未来方案的有效性。最突出的是寿命短在肿瘤特异性CTL的频率和功能上增加，特别是在患有笨重的疾病。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CTLS对TGF-B具有抗性，TGF-B是由HD肿瘤产生的免疫抑制分子，在复发性疾病的患者中将长时间持久和功能，（ii）肿瘤抗原（TA） - 表达IL-12的特定CTL将逆转TH2，而负免疫调节表型/功能肿瘤浸润的单核细胞和（iii）表达IL-12或本构T-bet的（III）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对和的抵抗力针对含有肿瘤的Th2和Treg的功效。这些预测将以三个特定的目的进行测试：确定采用转移的LMP1和LMP2特异性CTL的安全性和临床功效经过基因修饰，以表达跨性别的tgf-beta II型受体（DNR） EBV阳性高清或NHL（AIM 1）；评估经过转移的DNR基因修饰的功能持久性这些患者中的EBV-CTL（AIM 2）；并比较特异性的安全性和抗肿瘤功效在模仿人体高清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基因修饰证明是安全的，并增强了生存和功能 CTL在肿瘤部位，可以将该策略引入项目3和4中评估的T细胞疗法中。总结 - 在许多霍奇金疾病和非霍奇金淋巴瘤的患者中，癌细胞是感染了爱泼斯坦 - 巴尔病毒。淋巴瘤细胞中的病毒蛋白是对免疫疗法。该项目中的调查人员正在通过工程来利用这些病毒靶标特定类型的T细胞表达蛋白质，该蛋白质应提高修饰细胞找到的能力和破坏EBV阳性肿瘤而不会对患者产生毒性作用。