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

项目摘要 先天性巨细胞病毒（cCMV）感染，在子宫内获得，虽然是一种孤儿疾病（20- 80，000 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由于CMV基因组较大， 设计用于促进宿主抗病毒免疫应答的逃避、阻断、损害和调节， 出生时新生儿T细胞适应性免疫的不成熟和缺陷。这种适应不良的T细胞免疫反应， 出生是由子宫内时间和发育免疫失调引起的， 耐受性和预防母体免疫排斥，从而抑制正常T细胞成熟， 记忆T细胞对外来微生物抗原的发育。重要的是，弱CMV特异性T细胞适应性 免疫应答使患有宫内获得性cCMV的新生儿的严重 长期发病率和死亡率增加。至少暂时地恢复CD 4和CD 8特异性CMV T细胞， 因此，患有母体获得性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，并且代表未满足的需求。 我们之前已经建立了一个病毒细胞毒性T细胞淋巴细胞联盟（VIRTLC）， FDA孤儿补助金，用于在GMP条件下生产和富集单倍体相合（母体）供体来源的 使用CMV特异性Peptivator®和细胞因子捕获系统（CCS®）在Miltenyi上检测CMV特异性CTL CliniMACS®设备用于治疗患有原发性或继发性难治性/持续性CMV感染的婴儿和儿童 继发性T细胞缺乏症因此，我们假设制造母体供体来源的CMV CTL 在母体获得性cCMV的新生儿中进行后续给药将是可行、安全和有效的 与标准治疗（SOC）（缬更昔洛韦[valGCV]）联合治疗的患者相比， 这项FDA孤儿补助金提案的三个首要目标包括：1）确定可行性，安全性和 比较具有SOC与单独SOC的母体供体来源的CMV特异性CTL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和持久性以及比较 CMV CTL给药后先天性和适应性免疫景观的变化;和3）为了定量CMV CTL给药后先天性和适应性免疫景观的严重性和 两个治疗组之间长期神经系统后遗症和发育障碍的发生率。 CMV CTL将在GMP条件下使用CCS®制造，并每2周施用一次，直至 至5剂，valGCV × 6个月或单独valGCV。基因组学和免疫组学研究将由 ScRNAseq、质谱细胞术、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MRI、发育测试等进行测量。

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.