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首选治疗方法 以及其他危及生命的疾病，如原发免疫缺陷障碍(PID)。慢性 诺如病毒感染是造血干细胞移植的潜在并发症，可导致慢性腹泻和消瘦。确实有 目前还没有治疗诺沃克病毒的可用的疗法。我们已经证明健康的人有T细胞 对诺如病毒的免疫，以及NS6和VP1抗原中的病毒表位在病毒中被很好地保守 基因分型。这项提议的首要目标是开发一种治疗慢性诺沃克病毒的新方法。 接受造血干细胞移植患者的感染情况。在我们之前的研究中，我们证明了这种药物的安全性和潜在疗效。 针对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。要恢复 对诺沃克病毒的免疫力我们现在建议从健康的献血者身上采血，并扩大和丰富 献血者血液中存在的诺沃克病毒特异性T细胞(NSTs)，随后广泛描述了 NSTS的功能。然后，我们将给予NSTs作为治疗慢性诺沃克病毒的患者 HSCT。如果成功，这种新型的抗病毒疗法可以提供对诺沃克病毒的长期保护。因此，我们 假设输注NSTs将安全有效地对抗诺沃克病毒感染 HSCT，并将恢复对诺沃克病毒的持久免疫力。我们进一步假设，抗病毒疗效将 与识别免疫优势病毒表位的T细胞的扩张相关，这将对应于稳定 病毒基因组的区域。通过第一阶段的IND研究，我们将解决以下具体目标：1) 确定诺如病毒T细胞表位的广度和MHC限制，以及它们在 2)研究体外扩增T细胞靶向给药的安全性和可行性 作为治疗免疫低下患者慢性感染的诺沃克病毒，以及3)确定 输注NSTs可增强免疫低下宿主的诺如病毒特异性免疫。总而言之，这些 AIMS将确定NSTS是否可能是治疗患者慢性诺沃克病毒感染的安全有效的方法 HSCT后。这项研究的完成可能会提供一种新的抗病毒疗法，可以减少病毒- HSCT的相关发病率，并将指导未来针对肠道病毒的细胞治疗和疫苗试验。

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.