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

造血干细胞移植后过继性 T 淋巴细胞注射用于慢性诺如病毒治疗

基本信息

批准号：
10621950
负责人：
Michael Daniel Keller
金额：
$ 71.56万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621950
关键词：
16S ribosomal RNA sequencing Adenoviruses Adoptive Transfer Alleles Antigens Antiviral Response Antiviral Therapy Biological Assay Blood Blood donor CD8B1 gene Capsid Proteins Cell Therapy Cells Chronic Chronic diarrhea Clinical Collaborations Complication Cytomegalovirus Data Development Diarrhea Disease Disease Outbreaks Dose Enteral Epidemic Epitope Mapping Epitopes Feces Flow Cytometry Future Gastroenteritis Genetic Genotype Goals Hematopoietic Stem Cell Transplantation Hepatotoxicity Hospitalization Human Human Herpesvirus 4 Immune Immunity Immunocompromised Host Immunologic Deficiency Syndromes Individual Infection Infusion procedures Interferon Type II Knock-out Life Malabsorption Syndromes Malignant - descriptor Malignant Neoplasms Modeling Monitor Morbidity - disease rate Mus National Institute of Allergy and Infectious Disease Non-Malignant Norovirus Patient Transfer Patients Peptide Hydrolases Peptides Phase Quality of life RNA Viruses Reporting Safety Sorting Splenocyte Spottings Surveys T cell response T cell therapy T-Lymphocyte T-Lymphocyte Epitopes TRB@ gene cluster Testing Therapeutic Therapy trial Toxic effect Transplant Recipients United States National Institutes of Health Vaccinated Vaccines Variant Villous Atrophy Viral Viral Genome Viral Physiology Virion Virus Virus Diseases Viviparous-1 protein anti-viral efficacy chronic infection congenital immunodeficiency cytotoxicity disorder control effective therapy fecal microbiome gastrointestinal symptom improved in silico in vivo insight next generation sequencing novel novel therapeutics perforin phase I trial prediction algorithm response safety and feasibility safety study seropositive tool treatment choice vaccine development vaccine trial wasting

项目摘要

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.

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，例如原发性免疫缺陷病（PID）。慢性的诺如病毒感染是 HSCT 的潜在并发症，可导致慢性腹泻和消瘦。有目前尚无治疗诺如病毒的可用疗法。我们已经证明健康个体具有 T 细胞对诺如病毒的免疫力，并且抗原 NS6 和 VP1 中的病毒表位在病毒中非常保守基因型。该提案的总体目标是开发一种针对慢性诺如病毒的新型治疗方法接受 HSCT 的患者发生感染。在我们之前的研究中，我们证明了安全性和潜在功效针对 CMV、EBV 和腺病毒的病毒特异性 T 细胞以及该方法的可行性。恢复针对诺如病毒的免疫力，我们现在建议从健康献血者那里采集血液，并扩大和丰富诺如病毒的免疫力诺如病毒特异性 T 细胞 (NST) 存在于献血者的血液中，随后对其进行了广泛的表征 NST 的功能。然后，我们将为患有慢性诺如病毒的患者提供 NST 作为治疗方法造血干细胞移植。如果成功，这种新型抗病毒疗法可以提供针对诺如病毒的长期保护。因此，我们假设输注 NST 对术后患者诺如病毒感染是安全有效的 HSCT，将恢复对诺如病毒的持久免疫力。我们进一步假设抗病毒功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。通过这一 I 期 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 限制的广度，以及它们在临床病毒分离株，2) 研究体外扩增 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 可以增强免疫受损宿主的诺如病毒特异性免疫力。总的来说，这些目标将确定 NST 是否可以成为治疗慢性诺如病毒感染患者的安全有效的方法造血干细胞移植后。这项研究的完成可以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。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

SARS-CoV-2-specific T cells are rapidly expanded for therapeutic use and target conserved regions of the membrane protein.

DOI：
10.1182/blood.2020008488
发表时间：
2020-12-17
期刊：
Blood
影响因子：
20.3
作者：
Keller MD;Harris KM;Jensen-Wachspress MA;Kankate VV;Lang H;Lazarski CA;Durkee-Shock J;Lee PH;Chaudhry K;Webber K;Datar A;Terpilowski M;Reynolds EK;Stevenson EM;Val S;Shancer Z;Zhang N;Ulrey R;Ekanem U;Stanojevic M;Geiger A;Liang H;Hoq F;Abraham AA;Hanley PJ;Cruz CR;Ferrer K;Dropulic L;Gangler K;Burbelo PD;Jones RB;Cohen JI;Bollard CM
通讯作者：
Bollard CM