CMV, ADV and EBV Viral Cytotoxic T-Lymphocytes Generated by a Novel Cytokine Capture System in Children, Adolescents and Young Adults with Refractory Viral Infection and T-Cell Immunodeficiency

新型细胞因子捕获系统在患有难治性病毒感染和 T 细胞免疫缺陷的儿童、青少年和年轻人中产生 CMV、ADV 和 EBV 病毒细胞毒性 T 淋巴细胞

• 批准号: 10013179
• 负责人: Mitchell S. Cairo
• 金额: $ 42.45万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013179
• 关键词: CMV; ADV; EBV; Viral; Cytotoxic

Project Summary Children, adolescents and young adults (CAYA) with a primary T-cell immunodeficiency (PID) and/or secondary T-cell immunodeficiency following allogeneic stem cell transplantation (AlloSCT) and a medically refractory CMV, ADV and/or EBV infection and/or who become intolerant to antiviral antibiotics have a dismal prognosis (≥90% mortality rate). Refractory infections with CMV, ADV and EBV are uncommon and this represents an Orphan Disease (approximately 250 patients) in the United States. Strikingly, there is no FDA approved therapy for this rare patient population. Recently, adoptive T-cell therapy with viral specific cytotoxic T-lymphocytes (CTLs) is currently under early phase clinical investigations. This approach utilizes a rapid technique of viral specific CTL isolation following specific stimulation of donor peripheral blood mononuclear cells with viral-derived peptides followed by CTL isolation utilizing an INF-g Cytokine Capture System (Miltenyi Prodigy). In a small number of patients in single center studies, this approach has been feasible, safe and efficacious. The feasibility, safety and efficacy of this novel cellular therapy approach in this orphan population in larger multicenter prospective studies is presently lacking. We therefore hypothesize that partially HLA matched (haploidentical) related donor derived CMV, ADV and EBV CTLs manufactured utilizing the Miltenyi CliniMACS Prodigy Cytokine Capture System will be feasible, safe and effective in CAYA with either PID and/or SID following AlloSCT with medically refractory viral infections and/or those intolerant to antiviral antibiotics. We will investigate this hypothesis through three large multicenter viral CTL trials (IND17449) via the Viral CTL Consortium (VIRCTLC). The specific primary and secondary aims include (Brief): 1) feasibility and safety of CMV, ADV and EBV CTL production and infusion; 2) efficacy of viral specific CTLs (elimination of specific viral load by qRT-PCR below the lower limit of institutional values; 3) persistence of haploidentical donor viral CTL infusion; secondary: 4) probability of developing AGVHD; 5) probability of viral free and overall survival; 6) characterization of the genetic, proteomic and immunological properties of CMV, ADV and EBV CTLs; and 7) specific T-cell immune reconstitution, function and correlation to response to viral cell therapy. The experimental design including (brief): 1) viral CTL production by direct isolation following viral specific peptide stimulation and cytokine capture isolation; 2) three phase II open label prospective studies; 3) viral CTL validation and functionality; 4) viral CTL persistence by CD3 donor chimerism; and 5) viral CTL characterization by flow cytometry, mass cytometry by time of flight (CYTOF), single cell cytokine analysis, phosphoproteomics analysis, T-cell immunoprofiling, T cell receptor (TCR) diversity and frequency by Immunoseq, and single cell mRNA sequencing. The long term objectives are to obtain the feasibility, safety and efficacy of this therapy that will lead to FDA approval of CMV, ADV and EBV viral CTLs manufactured by the Miltenyi CliniMACS Prodigy Cytokine Capture System in this orphan patient population.

项目摘要 患有原发性T细胞免疫缺陷（PID）和/或 异基因造血干细胞移植（AlloSCT）后继发性T细胞免疫缺陷和药物治疗 难治性CMV、ADV和/或EBV感染和/或对抗病毒抗生素不耐受的患者， 预后（死亡率≥90%）。CMV、ADV和EBV的难治性感染并不常见， 代表美国的孤儿病（约250例患者）。令人惊讶的是， 用于这种罕见患者人群的获批治疗。最近，具有病毒特异性细胞毒性的过继性T细胞治疗被广泛应用。 T淋巴细胞（CTL）目前处于早期临床研究中。这种方法利用了快速 特异性刺激供体外周血单个核细胞后分离病毒特异性CTL技术 用病毒衍生的肽分离细胞，然后利用INF-g细胞因子捕获系统（Miltenyi Prodigy）。在单中心研究的少数患者中，这种方法是可行的，安全的， 灵验。这种新型细胞治疗方法在该孤儿人群中的可行性、安全性和有效性 目前缺乏更大规模的多中心前瞻性研究。因此，我们假设部分HLA 使用Miltenyi生产的匹配（单倍相合）相关供体衍生的CMV、ADV和EBV CTL CliniMACS Prodigy细胞因子捕获系统在采用任一PID的CAYA中均可行、安全且有效 和/或患有医学难治性病毒感染和/或对抗病毒药物不耐受的患者在AlloSCT后发生SID 抗生素我们将通过三项大型多中心病毒CTL试验（IND 17449）研究这一假设， 病毒CTL联盟（Viral CTL Consortium，VIRCTLC）具体的主要和次要目标包括（简要）：1）可行性 CMV、ADV和EBV CTL产生和输注的安全性; 2）病毒特异性CTL的功效（消除 通过qRT-PCR测定的特异性病毒载量低于机构值的下限; 3）单倍性一致性的持续性 供体病毒CTL输注;次要：4）发生AGVHD的可能性; 5）无病毒和总体 CMV、ADV和EBV的遗传、蛋白质组学和免疫学特性的表征 CTL;和7）特异性T细胞免疫重建、功能和与对病毒细胞疗法的应答的相关性。 实验设计包括（简述）：1）病毒特异性杀伤后直接分离产生病毒CTL 肽刺激和细胞因子捕获分离; 2）三项II期开放标签前瞻性研究; 3）病毒CTL 验证和功能性; 4）通过CD 3供体嵌合体的病毒CTL持久性;和5）病毒CTL 通过流式细胞术、飞行时间质谱细胞术（CYTOF）、单细胞细胞因子分析表征， 磷酸蛋白质组学分析，T细胞免疫谱，T细胞受体（TCR）的多样性和频率， Immunoseq和单细胞mRNA测序。长期目标是获得可行性、安全性 该疗法的有效性将导致FDA批准CMV、ADV和EBV病毒CTL， Miltenyi CliniMACS Prodigy细胞因子捕获系统用于该孤儿患者人群。