Probiotics for Prevention of Acute Graft-vs-Host Disease in Children with Cancer

项目摘要 尽管预防性免疫抑制，但临床显著（II-IV级）急性移植物抗宿主病 在接受异基因造血细胞移植的儿科患者中， （alloHCT）。由于aGvHD导致alloHCT后近20%的死亡，因此需要更好的预防 并且aGvHD的治疗是显而易见的。发病机制涉及胃肠道（GI） 已经通过临床前和临床研究的翻译证实了aGvHD的存在。新出现的证据 表明微生物群多样性的扰动导致异常的全身免疫反应， 病原体定殖和粘膜侵入，促进GvHD的发展。临床前研究还 提示在HCT前补充乳酸杆菌等益生菌可显著降低GvHD严重性 和肠道损伤。我们的试验数据表明，益生菌是安全的管理之前和期间的儿童 和接受HCT的青少年（IND #108，977）。本方案为双盲、随机、多中心 干预试验，以评估益生菌在预防GI aGvHD中的具体效果，更一般地， 对总体GvHD严重程度的影响。该提案是儿童肿瘤学小组（COG）批准的概念， NCI国家临床试验网络组。本研究将通过COG使用其临床 研究基础设施。将进行相关实验室研究（血浆和粪便分析），以 阐明益生菌疗法的作用机制。益生菌植物乳杆菌（LBP）或 将对384名接受alloHCT的可评价儿童和青少年给予安慰剂， 从开始预处理至第56天的恶性肿瘤。我们假设维持 通过给予益生菌治疗的上皮细胞完整性将导致恢复微生物多样性， 其将保持免疫耐受性并防止aGvHD。主要研究目的是确定 口服LBP预防儿童和青少年发生GI aGvHD 用于治疗癌症的alloHCT。次要研究目的是：（1）确定口服给药是否 LBP降低alloHCT后II-IV级aGvHD的发生率;（2）确定LBP是否 通过测定平均血浆瓜氨酸水平和降低肠内毒素水平， 粘膜屏障损伤（MBI）菌血症;（3a）测量LBP对肠道植物群系统发育的影响 使用16 S rRNA基因深度测序，在alloHCT期间和之后测定LBP的组成;（3b）测量LBP的作用 使用宏基因组学和代谢物谱分析在alloHCT期间和之后对肠道植物群功能的影响;以及（4） 测量LBP在同种异体反应诱导的平均血浆水平中的拟议免疫调节作用 与安慰剂相比，接受LBP的患者中的炎性细胞因子（IL-2、IL-6、IL-12 p70、IFNγ和TNFα）。 这项拟议的研究将是第一个双盲随机对照试验，以评估 益生菌预防儿科HCT中GI aGvHD。如果观察到有益效果， 对其他需要alloHCT的儿童和成人恶性疾病的拟议干预可能会总体改善 生活质量和预防移植相关并发症，如aGvHD。

Project Summary Despite prophylactic immune suppression, clinically significant (Grade II–IV) acute graft-versus-host disease (aGvHD) afflicts up to 45% of pediatric patients receiving allogeneic hematopoietic cell transplantation (alloHCT). As aGvHD is responsible for nearly 20% of deaths following alloHCT, the need for better prevention and therapy for aGvHD is readily apparent. Involvement of the gastrointestinal (GI) tract in the pathogenesis of aGvHD has been substantiated by the translation of pre-clinical and clinical studies. Emerging evidence suggests that perturbations in the microbiota diversity result in aberrant systemic immune response as well as pathogen colonization and mucosal invasion, fostering the development of GvHD. Pre-clinical studies also suggest that replenishing commensals like Lactobacillus prior to HCT substantially decrease GvHD severity and intestinal insult. Our pilot data suggest that probiotics are safe to administer prior to and during children and adolescents undergoing HCT (IND#108,977). This proposal is a double-blind, randomized, multi-center intervention trial to evaluate the specific effect of probiotics in preventing GI aGvHD and more generally the effects on overall GvHD severity. The proposal is an approved concept of Children’s Oncology Group’s (COG), a NCI National Clinical Trial Network group. The study will be conducted through COG using its clinical research infrastructure. Correlative laboratory studies (plasma and stool analysis) will be performed in order to elucidate the mechanisms of action of probiotic therapy. The probiotic, Lactobacillus plantarum (LBP), or placebo will be administered to 384 evaluable children and adolescents undergoing alloHCT for hematologic malignancy beginning with the initiation of conditioning through Day 56. We hypothesize that maintaining epithelial cell integrity through the administration of probiotic therapy will lead to restoring microbial diversity, which will preserve immune tolerance and prevent aGvHD. The primary study aim is to determine efficacy of orally-administered LBP in preventing the development of GI aGvHD in children and adolescents undergoing alloHCT for the treatment of cancer. Secondary study aims are: (1) To determine whether orally-administered LBP decreases the incidence of Grade II–IV aGvHD following alloHCT; (2) To determine whether LBP administration maintains intestinal integrity as measured by mean plasma citrulline levels and reduction in mucosal barrier injury (MBI) bacteremia; (3a) To measure the effects of LBP on the intestinal flora phylogenetic composition during and after alloHCT using 16S rRNA gene deep sequencing; (3b) To measure effects of LBP on intestinal flora function during and after alloHCT using metagenomic and metabolite profiling; and (4) To measure proposed immunomodulatory effects of LBP in mean plasma levels of alloreactive-induced inflammatory cytokines (IL-2, IL-6, IL-12p70, IFNγ, and TNFα) in patients receiving LBP compared to placebo. The proposed study will be the first double-blind randomized controlled trial to evaluate the effect of probiotics in preventing GI aGvHD in pediatric HCT. If a beneficial effect is observed, expansion of the proposed intervention to other pediatric and adult malignant conditions requiring alloHCT may improve overall quality of life and prevent transplant-related complications like aGvHD.