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，临床显著的(II-IV级)急性移植物抗宿主病 接受异基因造血细胞移植的儿童患者中高达45%患有(AGvHD) (AllHct)。由于异基因血细胞移植后近20%的死亡是由aGvHD造成的，因此需要更好的预防 对aGvHD的治疗是显而易见的。胃肠道受累在发病机制中的作用 AGvHD的临床前研究和临床研究的翻译已经证实。新出现的证据 表明微生物区系多样性的扰动会导致异常的全身免疫反应以及 病原菌定植和粘膜侵袭，促进了GvHD的发展。临床前研究也 建议在HCT前补充乳酸菌等共生菌可显著降低GvHD的严重程度 和肠道侮辱。我们的试验数据表明，益生菌在儿童之前和期间使用是安全的。 和接受HCT的青少年(IND#108,977)。该方案是双盲、随机、多中心的 评价益生菌预防胃肠道移植物抗宿主病的特殊效果的干预试验 对整体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国家临床试验网络小组。这项研究将通过COG进行，使用其临床 研究基础设施。将进行相关的实验室研究(血浆和大便分析)，以便 阐明益生菌治疗的作用机制。益生菌植物乳杆菌(LBP)，或 384名接受异基因血细胞移植的儿童和青少年将接受安慰剂治疗 恶性从条件作用的开始一直持续到第56天。我们假设维持 通过给予益生菌治疗保持上皮细胞的完整性将导致恢复微生物多样性， 这将保持免疫耐受性并防止aGvHD。研究的主要目的是确定其疗效 口服LBP预防儿童青少年胃肠道移植物抗宿主病的研究 用于治疗癌症的异基因血细胞移植。二次研究的目的是：(1)确定口服 LBP降低异基因HCT后II-IV级aGvHD的发生率；(2)确定LBP是否 通过平均血浆瓜氨酸水平和降低血浆中的 黏膜屏障损伤(MBI)菌血症；(3a)测定LBP对肠道菌群系统发育的影响 应用16S rRNA基因深度测序技术测定异体红细胞移植中和术后成分；(3b)测定LBP的作用 用代谢组学和代谢物图谱研究同种异体红细胞移植期间和术后肠道菌群功能； 测定LBP对同种异体反应诱导的血浆平均水平的免疫调节作用 接受LBP治疗的患者与安慰剂患者的炎性细胞因子(IL-2、IL-6、IL-12p70、干扰素γ和肿瘤坏死因子α)的比较。 这项拟议的研究将是第一个双盲随机对照试验，以评估 益生菌在预防儿童HCT中胃肠道移植物抗宿主病中的作用。如果观察到有益的效果，则扩展 建议对需要异基因红细胞移植的其他儿童和成人恶性疾病进行干预可能会改善总体情况 提高生活质量，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.