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: 9788275
• 负责人: Catherine M. Bollard
• 金额: $ 49.42万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9788275
• 关键词: Adenoviruses; Adoptive Transfer; Adult; Allogenic; Antibody Therapy; Antiviral Agents; BK Virus; Berlin; CCR5 gene; Cell Transplantation; Cell Transplants; 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; Participant; Patient Monitoring; Patients; Peptides; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; 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; Stem cells; 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; 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.

项目摘要 由于巨细胞病毒（CMV），爱泼斯坦 - 巴尔病毒（EBV），腺病毒（AD）和BK病毒（BKV）引起的病毒感染（BKV） 在接受同种异体造血干细胞的患者中仍是治疗失败的重要原因 移植（HSCT）。患有艾滋病毒的人需要进行基础恶性肿瘤 病毒反弹的高风险。脐带血（CB）或来自病毒的供体的HSC的接受者处于 由于其移植物没有病毒特异性记忆T细胞，因此特殊风险。抗病毒药仅对 一些病毒，大多数病毒具有明显的毒性。病毒特异性细胞毒性T淋巴细胞的过继转移 （VST）从干细胞供体中证明是安全且高效的，但通常仅用于 病毒经验供体的移植物的接受者，从而排除了风险最高的患者。缺乏 从幼稚的供体来源（例如CB）激活和扩展病毒特异性T细胞的有效策略已是 将方法扩展到高风险接收者的主要障碍，他们的发病率延长和 病毒疾病的高死亡率大大降低了移植程序的益处：益处。在 最后的资金周期，我们开发了一种新颖的方法，该方法有效地扩展了针对（CMV）的VST，（EBV） （AD）来自幼稚的CB衍生的T细胞。针对三种病毒的CB-VST具有广泛的表位特异性，是 单脐血后的12例儿科患者安全有效地预防和/或治疗的病毒感染 移植（CBT）。为了扩大这种方法的适用性，我们现在建议研究：（i）扩展此处 其他病毒（例如BKV和HIV）的方法，（ii）员工制造方案更快，（iii） 双重无关CBT（DUCBT）后，评估成人患者的VST治疗。因此，我们现在假设这一点， CBT之后，靶向四种病毒（CMV，EBV，AD，， BKV）将是安全的（AIM 1），并早点提供广泛的保护（<60天），以防止引起的病毒感染。 DUCBT（AIM 2）。我们进一步假设这种方法将有效地启动HIV特异性T- 来自CB的细胞，可能是CBT的治疗策略（AIM 3）。我们产生的结果将显示是否 这种新型策略可以始终产生针对最常见病原病毒之后的有效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 移植。我们的演示在最后一个资金周期中，自适应转移的安全性和可行性 接受CBT的儿科患者的VST为与项目1和3的合作奠定了基础 （在CB扩张/归纳和CB-NK细胞的临床试验中，T细胞的纵向T细胞重建，显着和 脉络化）以及项目4，其嵌合抗原受体靶向方法可用于 基因修改VST以使其针对常规病毒表位具有特异性。