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)感染是在宫内获得的，尽管是一种孤儿疾病(20-80,000 美国的病例/年)是美国最常见的先天性感染，也是导致 神经发育障碍。CCMV感染占所有与CMV相关的儿童死亡的41%。这 高发病率和高死亡率在很大程度上是继发于CMV大基因组，其基因是 旨在促进逃避、阻断、损害和调节宿主抗病毒免疫反应和 新生儿出生时T细胞适应性免疫功能的不成熟和缺陷。这种不适应的T细胞免疫反应 分娩是由宫内暂时性和发育性免疫失调导致的，导致对 耐受和预防母体免疫排斥，从而抑制正常T细胞成熟和 记忆T细胞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 免疫反应使宫内获得性CCMV新生儿患严重疾病的风险显著增加 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，母亲获得性CCMV新生儿的细胞免疫对于根除持续性CCMV至关重要， 难治性和/或抗药性巨细胞病毒感染和不良的长期后遗症，代表着未得到满足的需求。 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(VIRCTLC)，该联盟由一个 FDA孤儿赠款，在GMP条件下进行生产，并对单倍体相合(母体)供体来源的样品进行扩增 在Miltenyi上使用CMV特异性Peptivator®和细胞因子捕获系统(CCS®)的CMV特异性CTL 用于治疗难治性/持续性CMV感染的婴儿和儿童的CliniMACS®设备 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 对母亲获得性CCMV的新生儿进行后续治疗将是可行、安全和有效的 联合标准护理(SOC)(valganciclovir[valGCV])与仅使用SOC治疗的患者进行比较。 FDA孤儿赠款提案的三个主要目标包括：1)确定可行性、安全性和 比较母体供者来源的CMV特异性CTL与SOC和单独SOC的疗效；2)鉴定 母源CMV CTL的基因组和免疫学特征及其持久性比较 CMV CTL接种后的先天性和获得性免疫状况；以及3)量化严重程度和 两组间长期神经后遗症和发育障碍的发生率。 CMV CTL将在GMP条件下使用CCS®制造，并每两周实施一次 至5剂，加用valGCV×6个月或单用valGCV。基因组和免疫学研究将由 ScRNAseq、质量细胞术、高维流式细胞术和纳米线免疫分析。长期的 神经后遗症将通过听力图、大脑核磁共振、发育测试等来衡量。

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.