Multivirus-specific T Cells from Naive CB-derived T Cells

来自初始 CB 衍生 T 细胞的多病毒特异性 T 细胞

• 批准号: 10247040
• 负责人: Catherine M. Bollard
• 金额: $ 50.12万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-22 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247040
• 关键词: Adenoviruses; Adoptive Transfer; Adult; Allogenic; Antibody Therapy; Antiviral Agents; BK Virus; Berlin; CCR5 gene; Cell Therapy; Cell Transplantation; Cells; Clinical Protocols; Clinical Trials; Clinical Trials Network; Collaborations; Costs and Benefits; Cytomegalovirus; Cytomegalovirus Infections; Cytotoxic T-Lymphocytes; Disease; Enrollment; Epitopes; FDA approved; Funding; Gene Transfer; HIV; HIV Infections; HIV-1; Hematopoietic Stem Cell Transplantation; Homing; Human Herpesvirus 4; Immune; Immune system; Immunity; Immunotherapeutic agent; In Vitro; Incidence; Individual; Infection; Infusion procedures; Institutional Review Boards; International Maternal Pediatric Adolescent AIDS Clinical Trials; Life; Malignant Neoplasms; Morbidity - disease rate; Mutation; Natural Killer Cells; Natural Resistance; Participant; Patient Monitoring; Patients; Peptides; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase I/II Clinical Trial; Phase I/II Trial; Phenotype; Physiologic pulse; Population; Procedures; Process; Prophylactic treatment; Protocols documentation; Registries; Research; Research Personnel; Resistance; Resistance to infection; Risk; Source; Specificity; T cell reconstitution; T memory cell; T-Lymphocyte; Testing; Therapeutic; Time; Toxic effect; Transplantation; Treatment Failure; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Variant; Viral; Virus; Virus Diseases; adenovirus penton protein; antiviral immunity; chimeric antigen receptor; design; donor stem cell; effective therapy; ethnic minority population; experience; graft vs host disease; high risk; immune reconstitution; interest; lymphoblastoid cell line; lymphocyte product; mortality; novel; novel strategies; pathogenic virus; pediatric patients; post-transplant; prevent; receptor; reconstitution; safety and feasibility; success; transforming virus; validation studies; viral rebound

PROJECT SUMMARY Viral infections due to cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus (Ad) and BK virus (BKV) remain a significant cause of treatment failure in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Individuals living with HIV who require a transplant for an underlying malignancy are also at high risk for viral rebound. Recipients of cord blood (CB) or HSC from virus-naïve donors are at particular risk since their grafts contain no virus-specific memory T-cells. Antiviral drugs are effective only for some viruses, and most have significant toxicities. Adoptive transfer of virus-specific cytotoxic T lymphocytes (VSTs) from the stem cell donor has proved safe and highly effective, but has generally only been for recipients of grafts from virus-experienced donors, thereby excluding patients at highest risk. This lack of an effective strategy to activate and expand virus-specific T-cells from naïve donor sources such as CB, has been a major obstacle to extending the approach to high-risk recipients, whose continued prolonged morbidity and high mortality from viral diseases substantially reduces the cost:benefit ratio of the transplant procedure. In the last funding cycle, we developed a novel approach that effectively expanded VSTs specific for (CMV), (EBV) and (Ad) from naïve CB-derived T-cells. CB-VSTs targeting three viruses had broad epitope specificity, were safe and effectively prevented and/or treated viral infections in 12 pediatric patients after single cord blood transplantation (CBT). To broaden the applicability of this approach, we now propose studies to: (i) extend this approach to additional viruses (e.g. BKV and HIV), (ii) employ a more rapid manufacturing protocol and (iii) evaluate VST therapy in adult patients after double unrelated CBT (DUCBT). Hence, we now hypothesize that, following CBT, the infusion of rapidly manufactured CB-derived VSTs targeting FOUR viruses (CMV, EBV, Ad, BKV) will be safe (Aim 1) and provide broad protection early (< 60 days) against viral infections arising post- DUCBT (Aim 2). We further hypothesize that this approach will be effective for the priming of HIV-specific T- cells from CB, potentially as a curative strategy post-CBT (Aim 3). The results we generate will show whether this novel strategy can consistently produce effective VSTs directed to the commonest pathogenic viruses after CBT, including HIV, and whether this approach has the potential to reduce morbidity and mortality after transplantion. Our demonstration, during the last funding cycle, of the safety and feasibility of adoptive transfer of VSTs to pediatric patients undergoing CBT set the stage for collaborations with Projects 1 and 3 (longitudinal T-cell reconstitution in clinical trials of CB expansion/homing and of CB-NK cells, repectively and fucosylation) as well as Project 4, whose chimeric antigen receptor targeting approach could be used to genetically modify VSTs to render them specific for conventional virus epitopes.

项目概要 巨细胞病毒 (CMV)、EB 病毒 (EBV)、腺病毒 (Ad) 和 BK 病毒 (BKV) 引起的病毒感染 仍然是接受同种异体造血干细胞治疗的患者治疗失败的一个重要原因 需要移植治疗潜在恶性肿瘤的 HIV 感染者。 来自未接触过病毒的捐赠者的脐带血 (CB) 或 HSC 的接受者也面临着病毒反弹的高风险。 由于它们的移植物不含病毒特异性记忆 T 细胞，因此存在特别的风险，抗病毒药物仅对病毒有效。 一些病毒，并且大多数具有病毒特异性细胞毒性 T 淋巴细胞的过继转移。 来自干细胞捐赠者的（VST）已被证明是安全且高效的，但通常仅用于 移植物的接受者来自有病毒经历的捐赠者，从而排除了风险最高的患者。 激活和扩增来自幼稚供体来源（例如 CB）的病毒特异性 T 细胞的有效策略已被证实 将这种方法推广到高风险接受者的一个主要障碍，他们的发病率持续延长，并且 病毒性疾病的高死亡率大大降低了移植手术的成本效益比。 在上一个融资周期中，我们开发了一种新方法，可以有效扩展特定于 (CMV)、(EBV) 的 VST 和（Ad）来自针对三种病毒的幼稚 CB 衍生 T 细胞，具有广泛的表位特异性。 单脐带血治疗后 12 名儿科患者安全有效地预防和/或治疗病毒感染 为了扩大这种方法的适用性，我们现在建议进行以下研究：（i）扩展这种方法。 处理其他病毒（例如 BKV 和 HIV）的方法，(ii) 采用更快速的生产方案，并且 (iii) 评估成年患者在双重无关 CBT (DUCBT) 后的 VST 治疗因此，我们现在对此进行竞争。 CBT 后，注射快速制造的 CB 衍生 VST，针对四种病毒（CMV、EBV、Ad、 BKV）将是安全的（目标 1），并能在早期（< 60 天）提供广泛的保护，防止术后发生的病毒感染。 DUCBT（目标 2）：我们进一步认为这种方法对于启动 HIV 特异性 T- 是有效的。 来自 CB 的细胞，可能作为 CBT 后的治疗策略（目标 3）。 这种新策略可以持续产生针对最常见病原病毒的有效 VST CBT，包括艾滋病毒，以及这种方法是否有可能降低发病率和死亡率 我们在上一个资助周期中证明了收养转移的安全性和可行性。 为接受 CBT 的儿科患者提供 VST 为与项目 1 和 3 的合作奠定了基础 （CB 扩增/归巢和 CB-NK 细胞临床试验中的纵向 T 细胞重建，分别和 岩藻糖基化）以及项目 4，其嵌合抗原受体靶向方法可用于 对 VST 进行基因修饰，使其针对常规病毒表位具有特异性。