Improving T Cell Therapies for Nasopharyngeal Cancer

EB病毒(EBV)潜伏感染与鼻咽癌(NPC)有关。 表达EBV抗原LMP1、LMP2、EBNA1和BARF1，它们都是免疫治疗的潜在靶点。 项目4(S.Gottschalk和H.Heslop)和其他地方的调查人员已经表明， EBV特异性细胞毒性T细胞(EBV-CTL)是安全且具有抗肿瘤活性的，临床反应 与CTL产物中LMP2特异性T细胞的存在相关。尽管如此，反NFC活动 由申请人的当前方法产生的CTL线受以下几个因素的限制：(1)在 主要EBV源性肿瘤相关抗原LMP2特异性CTL群体的存在 T细胞对其他EBV相关肿瘤抗原-LMP1、EBNA1和 BARF1；(2)输注的CTL对免疫抑制肿瘤微环境的敏感性；以及(3) CTL不能攻击存在于头颈部癌症(包括鼻咽癌)中的反应性间质。中环 这个项目背后的假设是，消除上述两个或更多障碍将 增强输注CTL的抗肿瘤活性，改善鼻咽癌患者的预后。因此， 研究人员计划实施一种新的T细胞制造策略，持续生产T细胞 针对LMP2和至少其他三种鼻咽癌相关EBV抗原中的一种(鼻咽癌特异性CTL)。 他们还将用显性负性受体(DNR)对T细胞进行基因修饰，使其对 转化生长因子-β的产生是包括鼻咽癌在内的肿瘤常用的免疫逃避策略。 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)中进行评估， 进一步调查以监测它们在体内的命运(目标2)。目标3将询问表达嵌合体的CTL 肿瘤间质特异的抗原受体(CAR)，具有通过其靶向肿瘤细胞的能力 在小鼠异种移植模型中，天然受体将显示出增强的抗肿瘤活性。这些目标相辅相成 但不要与项目1-3中的项目重叠，这样我们研究中出现的进展可能是 迅速被同化为在该计划内的其他肿瘤中测试的策略，反之亦然。 相关性(请参阅说明)： 人体对癌症的免疫防御通常会失败，因为癌症不会诱发或主动 抑制免疫力。该项目的研究人员将试图通过设计杀手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。然后将在鼻咽癌(NPC)患者身上测试T细胞的效果。

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).