Immunotherapy for Hodgkin's Disease

霍奇金病的免疫疗法

基本信息

批准号：
7253715
负责人：
CLIONA M ROONEY
金额：
$ 23.24万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7253715
关键词：
Adoptive Transfer Aftercare Allogenic Amino Acids Animal Model Antigen Presentation Antigen Targeting Antigen-Presenting Cells Antigens Antitumor Response Apoptosis Attention Biopsy Biopsy Specimen Blood Bypass CTLA4 gene Catabolism Cell Line Cell physiology Cells Class Clinical Clinical Trials Conduct Clinical Trials Cytotoxic T-Lymphocytes Decitabine Defect Dendritic Cells Development Dinoprostone Dioxygenases Disease Disease remission Drug Formulations Drug usage Enrollment Environment Epitopes Frequencies Functional disorder Genes Hodgkin Disease Home environment Human Herpesvirus 4 Immune Immune system Immunocompetent Immunotherapy In Situ In Vitro Individual Infusion procedures LMP1 Long-Term Survivors Lymphocyte Function Lymphoma Malignant Neoplasms Malignant neoplasm of testis Maps Mediating Methods Modeling Morbidity - disease rate Mus Non-Hodgkin&apos s Lymphoma Patients Peptide Library Pharmaceutical Preparations Phase Phase I Clinical Trials Play Pre-Clinical Model Range Rate Reed-Sternberg Cells Regulation Relapse Reproduction spores Research Research Personnel Resistance Retroviral Vector Role Safety Scientist Small Interfering RNA Specificity Standards of Weights and Measures Starvation Stem cell transplant Stimulus T-Cell Activation T-Cell Proliferation T-Lymphocyte Testing Tissues Toxic effect Translating Transplant Recipients Tryptophan Tryptophan 2,3 Dioxygenase Tumor Antigens Tumor Cell Line Tumor Necrosis Factor Ligand Superfamily Member 6 Tumor Tissue Tumor-Derived Viral Antigens Virus biological adaptation to stress cancer cell chemotherapy cytokine cytotoxic eosinophil immunogenic improved in vivo killings knock-down monocyte neoplastic cell pathogen pre-clinical programs response success survivin tumor

项目摘要

Cytotoxic T-lymphocyte (CTL) therapy directed to Epstein-Barr virus (EBV) antigens has produced numerous and strong antitumor responses in patients with EBV-associated Hodgkin disease or non-Hodgkin lymphoma (NHL) without toxicity, but in the vast majority of cases the lymphoma cells do not express EBV antigens, obviating CTL therapy targeted to this virus. Moreover, virtually all standard treatments for Hodgkin disease and NHL impose high rates of morbidity that remain an issue for long-term survivors of these diseases. To extend CTL immunotherapy to all patients with relapsed lymphoma, regardless of the EBV status of their tumors, we have turned our attention to cancer testis antigens (CTAs), which are expressed by as many as 55% of the malignant cells in Hodgkin disease and survivin, which is expressed in the majority, and to strategies that might overcome the mechanisms that protect tumors from the cytotoxic effects of immunotherapy. Thus, in Aim 1, we propose to generate tumor-specific CTLs that recognize particular tumor antigens on EBV-negative Hodgkin tumors, such as survivin, MAGE-A4, SSX2, and SSX4, and then attempt to upregulate their expression on tumors by use of demethylating agents, including decitabine, both in vitro and in murine models. The safety, function and persistence of adoptively transferred CTA-specific CTL lines generated in Aim 1will be assessed in a Aim 2 in a Phase I trial enrolling patients with relapsed Hodgkin disease. The patients will also receive any demethylating agents found to be effective in upregulating CTAs in animal models. Finally, Aim 3 seeks to genetically modify the CTA-specific CTL lines to become resistant to Fas/FasL-mediated apoptosis and to circumvent the lethal anti-CTL consequences of indoleamine2,3- dioxygenase (IDO) expression by dendritic cells. Although restricted to preclinical models initially, these studies will ultimately be translated to clinical trials conducted outside the SPORE mechanism. Lay summary: Effective use of the immune system to combat cancer has been difficult because cancer cells have few features that are easily recognized by immune cells, such as T lymphocytes. In this project, scientists help T lymphocytes to recognize these features and will also attempt to find ways to avoid the tactics used by tumor cells to bypass the killing effects of T lymphocytes.

针对 Epstein-Barr 病毒 (EBV) 抗原的细胞毒性 T 淋巴细胞 (CTL) 疗法已产生大量 EB 病毒相关霍奇金病或非霍奇金淋巴瘤患者具有强烈的抗肿瘤反应 (NHL) 无毒性，但在绝大多数情况下淋巴瘤细胞不表达 EBV 抗原，避免针对该病毒的 CTL 治疗。此外，几乎所有霍奇金病的标准治疗方法 NHL 的高发病率对于这些疾病的长期幸存者来说仍然是一个问题。到将 CTL 免疫治疗扩展到所有复发性淋巴瘤患者，无论其 EBV 状态如何肿瘤，我们已将注意力转向癌症睾丸抗原（CTA），该抗原由多种细胞表达 55%的恶性细胞在霍奇金病和存活蛋白中表达最多，并且可能克服保护肿瘤免受细胞毒性作用的机制的策略免疫疗法。因此，在目标 1 中，我们建议生成识别特定肿瘤的肿瘤特异性 CTL EBV 阴性霍奇金肿瘤上的抗原，例如生存素、MAGE-A4、SSX2 和 SSX4，然后尝试通过使用去甲基化剂（包括地西他滨）在体外上调它们在肿瘤上的表达以及在小鼠模型中。过继转移的 CTA 特异性 CTL 系的安全性、功能和持久性目标 1 中产生的结果将在招募霍奇金复发患者的 I 期试验的目标 2 中进行评估疾病。患者还将接受任何被发现能有效上调 CTA 的去甲基化药物在动物模型中。最后，目标 3 寻求对 CTA 特异性 CTL 系进行基因改造，使其具有抗性 Fas/FasL 介导的细胞凋亡并规避吲哚胺2,3- 的致命抗 CTL 后果树突状细胞表达双加氧酶（IDO）。尽管最初仅限于临床前模型，但这些研究最终将转化为在 SPORE 机制之外进行的临床试验。简单总结：有效利用免疫系统来对抗癌症一直很困难，因为癌细胞几乎没有易于被免疫细胞（例如 T 淋巴细胞）识别的特征。在这个项目中，科学家们帮助T淋巴细胞识别这些特征，并将尝试找到避免这些特征的方法。肿瘤细胞用来绕过 T 淋巴细胞杀伤作用的策略。