A Randomized Study of Maternal Donor Derived CMV Cytotoxic T-Lymphocytes (CTLs) and Valganciclovir vs Valganciclovir in Neonates With Moderate/Severe Maternal Acquired CMV Infection

母体供体来源的 CMV 细胞毒性 T 淋巴细胞 (CTL) 和缬更昔洛韦与缬更昔洛韦在中度/重度母体获得性 CMV 感染新生儿中的随机研究

• 批准号: 10730709
• 负责人: Mitchell S. Cairo
• 金额: $ 65万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730709
• 关键词: Randomized; Study; Maternal; Donor; Derived

Project Summary Congenital cytomegalovirus (cCMV) infection that is acquired in-utero, although an orphan disease (20-80,000 cases/yr in U.S.) is the most common congenital infection in the U.S. and the leading cause of long-term neurodevelopmental disabilities. cCMV infection represents 41% of all CMV associated childhood deaths. This high degree of morbidity and mortality is in large part secondary to the large CMV genome whose genes are designed to facilitate evasion, blocking, impairing and modulation of host anti-viral immune responses and an immaturity and deficit in neonatal T-cell adaptive immunity at birth. This maladaptive T-cell immune response at birth results from temporal and developmental immune dysregulation in-utero with a resulting bias towards tolerance and preventing maternal immunological rejection, thereby suppressing normal T-cell maturation and development of memory T-cells to foreign microbial antigens. Importantly, a poor CMV specific T-cell adaptive immune response predisposes neonates with cCMV acquired in-utero to a significant increased risk of serious long-term morbidity and increased mortality. Restoring, at least temporarily, both CD4 and CD8 specific CMV T- cell mediated immunity in neonates with maternal acquired cCMV is therefore critical to eradicating persistent, refractory and/or resistant CMV infection and undesirable long-term sequelae and represents an unmet need. We have previously established a Viral Cytotoxic T-Cell Lymphocyte Consortium (VIRCTLC) funded under an FDA Orphan Grant to manufacture under GMP conditions and enrich for haploidentical (maternal) donor-derived CMV specific CTLs utilizing a CMV specific Peptivator® and the cytokine Capture System (CCS®) on the Miltenyi CliniMACS® device for treatment of infants and children with refractory/persistent CMV infection with primary or secondary T-cell deficiencies. We, therefore, hypothesize that manufacturing maternal donor-derived CMV CTLs and subsequent administration in neonates with maternal acquired cCMV will be feasible and safe and effective in combination with standard of care (SOC) (valganciclovir [valGCV]) compared to those treated with SOC alone. The three overarching aims of this FDA orphan grant proposal includes: 1) To determine feasibility, safety and compare the efficacy of maternal donor-derived CMV specific CTLs with SOC vs SOC alone; 2) To characterize the genomic and immunomic signatures and persistence of maternal donor-derived CMV CTLs and comparison of innate and adaptive immune landscape post CMV CTL administration; and 3) To quantify the severity and incidence of long-term neurological sequelae and developmental disabilities between the two treatment groups. CMV CTLs will be manufactured under GMP conditions utilizing the CCS® and administered every 2 weeks up to 5 doses with valGCV x 6 months or valGCV alone. Genomic and immunomic studies will be performed by ScRNAseq, mass cytometry, high dimensional flow cytometry and Nanostring immunoprofiling. Long-term neurological sequelae will be measured by audiograms, brain MRIs, developmental testing, among others.

项目概要 先天性巨细胞病毒 (cCMV) 感染是在子宫内获得的，虽然是一种孤儿病 (20-80,000 病例/年（美国）是美国最常见的先天性感染，也是长期感染的主要原因 神经发育障碍。 cCMV 感染占所有 CMV 相关儿童死亡的 41%。这 高发病率和死亡率在很大程度上是继发于巨细胞病毒基因组，其基因为 旨在促进逃避、阻断、损害和调节宿主抗病毒免疫反应以及 新生儿出生时 T 细胞适应性免疫不成熟和缺陷。这种适应不良的 T 细胞免疫反应 出生是由于子宫内时间和发育免疫失调造成的，从而导致偏向 耐受性并防止母体免疫排斥，从而抑制正常 T 细胞成熟和 记忆T细胞针对外来微生物抗原的发育。重要的是，CMV 特异性 T 细胞适应性差 免疫反应使患有宫内感染 cCMV 的新生儿出现严重并发症的风险显着增加 长期发病率和死亡率增加。至少暂时恢复 CD4 和 CD8 特异性 CMV T- 因此，感染母体获得性 cCMV 的新生儿的细胞介导的免疫对于根除持续性、 难治性和/或耐药性 CMV 感染和不希望的长期后遗症，代表着未满足的需求。 我们之前已经建立了病毒细胞毒性 T 细胞淋巴细胞联盟 (VIRCTLC)，该联盟由 FDA 孤儿补助金将在 GMP 条件下生产并富集半相合（母体）供体来源 CMV 特异性 CTL，利用 Miltenyi 上的 CMV 特异性 Peptivator® 和细胞因子捕获系统 (CCS®) CliniMACS® 设备用于治疗患有原发性或持续性 CMV 感染的婴儿和儿童 继发性 T 细胞缺陷。因此，我们假设生产母体供体来源的 CMV CTL 随后对患有母体获得性 cCMV 的新生儿进行给药将是可行、安全和有效的 与单独使用 SOC 治疗的患者相比，联合标准护理 (SOC)（缬更昔洛韦 [valGCV]）治疗。 FDA 孤儿拨款提案的三个总体目标包括： 1) 确定可行性、安全性和 比较母体供体来源的 CMV 特异性 CTL 与 SOC 与单独 SOC 的功效； 2）表征 母体供体来源的 CMV CTL 的基因组和免疫组学特征以及持久性和比较 CMV CTL 给药后的先天性和适应性免疫景观； 3) 量化严重性和 两个治疗组之间长期神经后遗症和发育障碍的发生率。 CMV CTL 将在 GMP 条件下利用 CCS® 进行生产，并每两周给药一次 5 剂 valGCV x 6 个月或单独 valGCV。基因组和免疫组学研究将由 ScRNAseq、质谱流式细胞术、高维流式细胞术和 Nanostring 免疫分析。长期 神经系统后遗症将通过听力图、脑部核磁共振成像、发育测试等进行测量。