OVERCOMING TUMOR EVASION MECHANISMS IN HODGKIN DISEASE

由C.Rooney领导的Project 1的长期目标是改善免疫治疗的结果 与EB病毒相关的淋巴瘤，尤其是霍奇金病和非霍奇金 淋巴瘤(NHL)。尽管在前一个资助周期中的研究表明，细胞毒性T淋巴细胞 (CTL)针对EBV的LMP2蛋白，结合肿瘤部位并产生抗肿瘤作用(完整 在6名复发患者中有4名患者有反应)，这种治疗方法有明显的缺点，将限制其 对HD和NHL患者以及其他恶性肿瘤患者的未来方案的有效性。最突出的是 肿瘤特异性CTL的频率和功能的短暂增加，特别是在 大块头的疾病。这些观察表明，最佳免疫反应正受到 肿瘤微环境和肿瘤细胞本身，导致研究人员提出(I) 抗转化生长因子-B的LMP1和LMP2特异性CTL，转化生长因子-B是HD肿瘤产生的免疫抑制分子， 对复发性疾病患者具有持久的持久性和功能，(Ii)肿瘤抗原(TA)- 表达IL-12的特异性CTL将逆转Th2和阴性免疫调节表型/功能 肿瘤浸润性单个核细胞，以及(Iii)表达IL-12或结构性T-bet的TA特异性CTL， Tc1/Th1功能的主要调节者和GATA-3的抑制剂将增强对 对含有Th2和Treg的肿瘤的疗效。这些预测将在三个具体目标上得到检验： 过继转移的LMP1和LMP2特异性CTL的安全性和临床疗效 基因修饰表达跨显性阴性转化生长因子-βII型受体(DNR) EBV阳性HD或NHL(AIM 1)；评价过继转导的DNR基因修饰的功能持久性 这些患者中的EBV-CTL(目标2)；并比较TA特异性的安全性和抗肿瘤效果 在模拟人类HD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基因修饰被证明是安全的，并提高了小鼠的生存和功能 对于肿瘤部位的CTL，这一策略可以被引入到项目3和4中评估的T细胞疗法中。 在许多霍奇金病和非霍奇金淋巴瘤患者中，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吸引人的靶点 免疫疗法。这个项目的研究人员正在利用这些病毒靶标，通过设计一种 特定类型的T细胞表达的蛋白质应该可以提高修饰细胞的发现和识别能力 销毁EBV阳性肿瘤，不会对患者产生毒副作用。

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.