Adoptive T Lymphocyte Administration for Chronic Norovirus Treatment Following Hematopoietic Stem Cell Transplantation

造血干细胞移植（HSCT）是许多恶性肿瘤患者的治疗选择 以及其它威胁生命的病症，例如原发性免疫缺陷病症（PID）。慢性 诺如病毒感染是HSCT的潜在并发症，可引起慢性腹泻和消瘦。有 目前没有治疗诺如病毒的有效疗法。我们已经证明，健康的人有T细胞， 抗诺如病毒免疫力，且抗原NS 6和VP 1中的病毒表位在病毒间是很保守的 基因型该提案的总体目标是开发一种新的慢性诺如病毒治疗方法 接受HSCT的患者感染。在我们之前的研究中，我们证明了 靶向CMV、EBV和腺病毒的病毒特异性T细胞以及这种方法的可行性。恢复 我们现在建议从健康的献血者那里抽取血液，扩大和丰富 诺如病毒特异性T细胞（NST）存在于供体的血液中，随后对NST进行了广泛的表征。 NST的功能。然后，我们将给予NST作为慢性诺如病毒的治疗， HSCT。如果成功，这种新型抗病毒疗法可以提供长期保护，防止诺如病毒。因此我们 假设NST的输注将安全有效地对抗术后患者的诺如病毒感染， HSCT，并将恢复对诺如病毒的持久免疫力。我们进一步假设，抗病毒疗效将 与识别免疫显性病毒表位的T细胞的扩增相关，这将对应于稳定的 病毒基因组的区域。通过第一阶段IND研究，我们将实现以下具体目标：1） 确定诺如病毒T细胞表位和MHC限制的宽度，以及它们在体内的遗传稳定性。 研究体外扩增的T细胞靶向给药的安全性和可行性， 诺如病毒作为免疫功能低下患者慢性感染的治疗方法，以及3）确定是否 输注NST可增强免疫受损宿主中的诺如病毒特异性免疫。总的来说，这些 目的是确定NST是否可能是慢性诺如病毒感染患者的安全有效治疗方法 HSCT后。这项研究的完成可以提供一种新的抗病毒治疗，可以减少病毒- HSCT相关的发病率，并将指导未来的细胞治疗和针对肠道病毒的疫苗试验。

Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many patients with malignancies as well as other life-threatening conditions such as primary immunodeficiency disorders (PID). Chronic norovirus infection is a potential complication of HSCT, and can cause chronic diarrhea and wasting. There are currently no available therapies to treat norovirus. We have demonstrated that healthy individuals have T cell immunity against norovirus, and that viral epitopes in antigens NS6 and VP1 are well conserved across viral genotypes. The overarching goal of this proposal is the development of a novel treatment for chronic norovirus infection in patients undergoing HSCT. In our previous study, we demonstrated safety and potential efficacy of virus-specific T cells targeting CMV, EBV, and adenovirus as well as the feasibility of this approach. To restore immunity against norovirus we now propose to take blood from the healthy donors and expand and enrich the norovirus-specific T cells (NSTs) present in donors' blood, followed by extensive characterization of the function of NSTs. We will then give NSTs as treatment for chronic norovirus in patients who have undergone HSCT. If successful, this novel antiviral therapy could provide long-term protection against norovirus. Thus, we hypothesize that the infusion of NSTs will be safe and effective against norovirus infections in patients post HSCT, and will restore lasting immunity against norovirus. We further hypothesize that antiviral efficacy will correlate with expansion of T cells recognizing immunodominant viral epitopes, which will correspond to stable regions of the viral genome. Through this phase I IND study, we will address the following specific aims: 1) To determine the breadth of norovirus T cell epitopes and MHC restrictions, as well as their genetic stability in clinical viral isolates, 2) To study the safety and feasibility of administering ex vivo expanded T cells targeting norovirus as treatment of chronic infection in immunocompromised patients, and 3) To determine whether infusion of NSTs can enhance norovirus specific immunity in immune compromised hosts. Collectively, these aims will determine if NSTs may be a safe and effective treatment for chronic norovirus infection in patients post HSCT. Completion of this study could provide a novel antiviral therapy which could reduce virus- associated morbidity in HSCT, and will guide future cellular therapy and vaccine trials targeting enteric viruses.