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

• 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
• 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

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治疗选择

项目成果

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

SARS-COV-2特异性T细胞迅速扩展以供治疗用途，并靶向保守的膜蛋白。

• 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