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.

针对爱泼斯坦 - 巴尔病毒（EBV）抗原的细胞毒性T淋巴细胞（CTL）疗法已产生了许多 EBV相关霍奇金疾病或非霍奇金淋巴瘤患者的强烈抗肿瘤反应（NHL）没有毒性，但是在绝大多数情况下，淋巴瘤细胞不表达EBV抗原，消除针对该病毒的CTL疗法。而且，几乎所有有关霍奇金病的标准治疗方法 NHL施加了很高的发病率，对于这些疾病的长期幸存者来说，这仍然是一个问题。到不管其EBV状态如何肿瘤，我们将注意力转向癌症睾丸抗原（CTA），这些抗原由多大表达霍奇金疾病和遗传中的55％的恶性细胞在大多数中表达，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AIM 1中，我们建议生成识别特定肿瘤的肿瘤特异性CTL EBV阴性Hodgkin肿瘤上的抗原，例如Survivin，Mage-A4，SSX2和SSX4，然后尝试通过使用脱甲基剂（包括去甲他滨）的脱甲基化剂，都在体外上调它们在肿瘤上的表达和在鼠模型中。采用转移的CTA特异性CTL线的安全性，功能和持久性在AIM 1 Will中产生的AIM 2在I期试验中评估，招募Hodgkin的患者疾病。患者还将收到任何发现有效上调CTA的脱甲基化剂在动物模型中。最后，AIM 3试图在遗传上修改CTA特异性CTL线以变得抗性为FAS/FASL介导的凋亡，并规避吲哚胺的致命抗CTL后果2,3-- 树突状细胞表达二氧酶（IDO）。尽管最初仅限于临床前模型，但研究最终将转化为在孢子机制之外进行的临床试验。摘要摘要：有效利用免疫系统对抗癌症一直很困难，因为癌细胞很少有免疫细胞易于识别的特征，例如T淋巴细胞。在这个项目中，科学家帮助T淋巴细胞识别这些特征，还将尝试寻找避免这种特征的方法肿瘤细胞使用的策略绕过T淋巴细胞的杀伤作用。