Immunotherapy for Hodgkin's Disease

针对EB病毒(EBV)抗原的细胞毒性T淋巴细胞(CTL)治疗已产生大量 EBV相关霍奇金病或非霍奇金淋巴瘤患者的强烈抗肿瘤反应 (非霍奇金淋巴瘤)无毒，但在绝大多数病例中，淋巴瘤细胞不表达EBV抗原， 避免了针对这种病毒的CTL治疗。此外，几乎所有霍奇金病的标准治疗方法 和非霍奇金淋巴瘤的高发病率仍然是这些疾病的长期幸存者的一个问题。至 将CTL免疫治疗扩大到所有复发淋巴瘤患者，无论他们的EBV状态如何 肿瘤，我们已经将注意力转向癌症睾丸抗原(CTA)，它由多达 霍奇金病中55%的恶性细胞和Survivin在大多数情况下表达，并 可能克服保护肿瘤免受细胞毒作用的机制的策略 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阴性霍奇金肿瘤的抗原，如Survivin、MAGE-A4、SSX2和SSX4，然后尝试 使用去甲基化药物，包括地西他滨，在体外上调其在肿瘤上的表达 在小鼠模型中也是如此。过继转导CTA特异性CTL细胞系的安全性、功能性和持久性 在一项招募复发霍奇金患者的I期试验中，在AIM 1中产生的结果将在AIM 2中进行评估 疾病。患者还将接受任何被发现有效上调CTA的去甲基化药物。 在动物模型中。最后，Aim 3试图对CTA特异的CTL品系进行基因改造，使其具有抗药性 对Fas/FasL介导的细胞凋亡和绕过吲哚乙胺2，3-二氯甲烷的致死性抗CTL后果 树突状细胞表达双加氧酶。尽管最初仅限于临床前模型，但这些模型 研究最终将转化为在孢子机制之外进行的临床试验。 莱茵摘要：有效利用免疫系统与癌症作斗争一直很困难，因为癌细胞 几乎没有免疫细胞容易识别的特征，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，并将试图找到避免 肿瘤细胞绕过T淋巴细胞杀伤作用的策略。

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.