Improving T Cell Therapies for Nasopharyngeal Cancer

潜伏性EB病毒（EBV）感染与鼻咽癌（NPC）有关， 表达EBV抗原LMP 1、LMP 2、EBNA 1和BARF 1，所有这些都是免疫治疗的潜在靶标。 项目4的研究人员（S。Gottschalk和H. Heslop）和其他地方的研究表明， EB病毒特异性细胞毒性T细胞（EBV-CTL）是一种安全、有效的抗肿瘤细胞， 与CTL产物中LMP 2特异性T细胞的存在相关。尽管如此，反NFC活动 通过本申请人的现有方法产生的CTL系的变异性受到以下几个因素的限制：（1）在细胞中的变异性， 存在对主要EBV衍生的肿瘤相关抗原LMP 2具有特异性的CTL群体 和低频率的T细胞对其他EBV相关肿瘤抗原-LMP 1、EBNA 1和 BARF 1;（2）输注的CTL对免疫抑制性肿瘤微环境的敏感性;和（3）免疫抑制性肿瘤微环境的敏感性。 CTL不能攻击存在于头颈癌（包括NPC）中的反应性基质。中央 这一项目的假设是，消除上述两个或两个以上的障碍， 增强输注CTL的抗肿瘤活性，改善NPC患者的预后。因此 研究人员计划实施一种新的T细胞制造策略， 对LMP 2和其他三种NPC相关EB病毒抗原（NPC特异性CTL）中的至少一种具有特异性。 他们还将用显性负性受体（DNR）对T细胞进行遗传修饰，使其对 TGF-β，其产生是包括NPC在内的肿瘤使用的常见免疫逃避策略。 这些修饰的T细胞的安全性和抗肿瘤活性将在I期试验（Aim 1）中评估， 进一步研究以监测它们的体内命运（目的2）。目标3将询问表达嵌合体的CTL是否 抗原受体（CAR），其特异于肿瘤基质并具有通过其靶向肿瘤细胞的能力。 天然受体将在鼠异种移植模型中显示增强的抗肿瘤活性。这些目标补充了 但不要与项目1-3中的那些重叠，这样我们的研究中出现的进展就可以 在这个项目中，它迅速被吸收到其他肿瘤中测试的策略中，反之亦然。 相关性（参见说明）： 身体对癌症的免疫防御经常失败，因为恶性肿瘤不会诱导或主动 抑制免疫力。该项目的研究人员将试图通过工程杀手T来抵消这些限制 细胞识别癌细胞上的结构并抵抗肿瘤细胞施加的防御 环境T细胞的效果将在鼻咽癌患者中进行测试。

Latent Epstein-Barr virus (EBV) infection is associated with nasopharyngeal carcinoma (NPC), which expresses the EBV antigens LMP1, LMP2, EBNA1 and BARF1, all potential targets for immunotherapy. Investigators in Project 4 (S. Gottschalk and H. Heslop) and elsewhere have shown that administration of EBV-specific cytotoxic T cells (EBV-CTLs) is safe and has antitumor activity, and that clinical responses correlate with the presence of LMP2-specific T cells in the CTL product. Nonetheless, the anti-NFC activity of the CTL lines generated by the applicants' cun-ent methods is limited by several factors: (1) variability in the presence of CTL populations with specificity to the major EBV-derived tumor-associated antigen LMP2 and low frequency of T cells reactive to the other EBV-associated tumor antigens - LMP1, EBNA1 and BARF1; (2) the sensitivity of infused CTLs to the immunosuppressive tumor microenvironment; and (3) the inability of CTLs to attack the reactive stroma present in head and neck cancers, including NPC. The central hypothesis underiying this project is that eliminating two or more of the above obstacles will enhance the antitumor activity of infused CTLs, and improve the outcome in NPC patients. Thus, the investigators plan to implement a new T-cell manufacturing strategy that consistently produces T cells specific for LMP2 and at least one of the other three NPC-associated EBV antigens (NPC-specific CTLs). They will also genetically modify T cells with a dominant-negative receptor (DNR) to render them resistant to TGF-beta, the production of which is a common immune evasion strategy used by tumors including NPC. The safety and antitumor activity of these modified T cells will be evaluated in a phase I trial (Aim 1) with further investigations to monitor their in vivo fate (Aim 2). Aim 3 will ask if CTLs expressing a chimeric antigen receptor (CAR) specific for tumor stroma and having the capacity to target tumor cells through their native receptors will show enhanced antitumor activity in a murine xenograft model. These aims complement but do not overlap with those in Projects 1-3, such that advances emerging from our research could be rapidly assimilated into strategies being tested In other tumors within this program and vice versa. RELEVANCE (See instructions): The body's Immune defenses against cancers often fail because the malignancies do not induce or actively inhibit immunity. Investigators in this project will try to counteract these limitations by engineering killer T cells to recognize structures on cancer cells and to resist the defenses Imposed by the tumor cell environment. The effects ofthe T cells will then be tested in patients with nasopharyngeal carcinoma (NPC).