Immunotherapy for Hodgkin's Disease

霍奇金病的免疫疗法

• 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
• 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' 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

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EB病毒（EBV）抗原的细胞毒性T淋巴细胞（CTL）疗法已经产生了许多针对EB病毒（EBV）抗原的细胞毒性T淋巴细胞。 在EB病毒相关霍奇金病或非霍奇金淋巴瘤患者中， (NHL)没有毒性，但在绝大多数情况下，淋巴瘤细胞不表达EBV抗原， 避免了针对该病毒的CTL治疗。此外，几乎所有霍奇金病的标准治疗方法 和NHL造成高发病率，这对于这些疾病的长期幸存者来说仍然是一个问题。到 将CTL免疫疗法扩展到所有复发性淋巴瘤患者，无论其EBV状态如何， 为了检测肿瘤，我们将注意力转向了癌症睾丸抗原（CTA）， 霍奇金病中55%的恶性细胞和生存素，生存素在大多数中表达， 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，在目标1中，我们提出产生识别特定肿瘤的肿瘤特异性CTL， 抗原，如生存素、MAGE-A4、SSX 2和SSX 4，然后尝试 通过使用去甲基化剂，包括地西他滨， 和小鼠模型中。过继转移CTA特异性CTL细胞系的安全性、功能和持久性 在Aim 1中生成的将在Aim 2中进行评估，该I期试验招募了复发性霍奇金淋巴瘤患者 疾病患者还将接受发现在上调CTA中有效的任何去甲基化剂 在动物模型中。最后，目标3寻求遗传修饰CTA特异性CTL系以使其具有抗性 Fas/FasL介导的细胞凋亡和规避吲哚胺2，3- 树突状细胞的双加氧酶（IDO）表达。虽然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 具有很少容易被免疫细胞（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，并试图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。