Alemtuzumab treatment of steroid-refractory acute GvHD

描述(由申请人提供)：我们建议对异基因造血干细胞移植受者进行阿伦图珠单抗治疗激素难治性急性移植物抗宿主病的II期研究。尽管采取了标准的预防措施，但中到重度急性移植物抗宿主病(II-IV级)发生在30-50%的匹配亲缘受体和50-70%的非亲缘异基因移植物受体中。急性移植物抗宿主病也可发生在T细胞耗尽的同种异体移植后，尤其是来自不匹配的和/或无关的供者。II-IV级GvHD需要全身治疗，通常是大剂量的肠外类固醇。然而，这些患者中约有60%被证明是类固醇无效的，需要没有标准的、有效的选择的替代疗法。 我们最近发现，不同亚型的人树突状细胞(DC)选择性地表达CD52，它是阿伦图珠单抗靶向的。单核细胞来源的DC(MoDC)表达CD52，而郎格汉斯细胞(LCs)和真皮间质DC(DDC-IDCs)则不表达CD52表位，无论是作为正常组织或炎症组织的驻留群体，还是作为细胞因子产生的CD34+HPC的子代。尽管移植前给予阿伦图珠单抗可消除宿主moDC而不影响供体moDC的植入，但移植后给予alemtuzumab对供者moDC的影响尚不清楚。MoDC是吞噬能力最强的DC，因此最有能力从死亡细胞中摄取宿主AGs，用于交叉呈递到移植供体T细胞。因此，antJ-CD52治疗GvHD的有益效果可能不仅来自于它对同种异体激活的T细胞的消耗，也来自于选择性地清除GvHD炎症环境中的moDC。抗CD52治疗后LCs和DDC-IDCs的保存可能使这些DC在获得性免疫和有益免疫的再发展中发挥形成作用。这与Daclizumab(抗CD25)或胸球蛋白/ATG治疗后的结果不同，这两种治疗方法都是以大多数或全部单核细胞和DC为靶标。以及T细胞。 我们认为GvHD与移植物-宿主耐受、细胞免疫重建和异基因HSCT带来的GVT益处是分开的，所有这些都是在DC提呈抗原的水平上的。我们将(1)通过选择性靶向moDC和T细胞来确定alemtuzumab在激素难治性急性GvHD中实现应答的有效性：(2)评估alemtuzumab是否发挥了类固醇节省效应，消除了其他挽救疗法的必要性，降低了慢性GvHD的发生率，并改善了OS和DFS；以及(3)定量GvHD血清/血浆中的炎性细胞因子的循环水平，这些细胞因子反过来可能支持DC的激活和针对宿主同种异体抗原的供体T细胞的刺激；以及计数循环中NK、NKT和T-reg细胞以及循环和组织驻留的CD52 pos/neg DC群体的变化。我们预测，alemtuzumab将有效地治疗激素难治性急性GvHD，防止复发，并允许在没有大剂量类固醇持续免疫抑制的情况下更正常地进行免疫重建。

DESCRIPTION (provided by applicant): We propose a phase II study of alemtuzumab for the treatment of steroid-refractory acute graft-vs.-host disease in recipients of allogeneic hematopoietic stem cell allografts. Moderate to severe acute GvHD (grades II-IV) occurs in 30-50% of matched related recipients and 50-70% of unrelated recipients of unmodified allografts, despite standard prophylaxis. Acute GvHD can also occur after T cell-depleted allografts, especially from HLA-mismatched and/or unrelated donors. Grade II-IV GvHD requires systemic therapy, typically high dose parenteral steroids. Approximately 60% of these patient prove steroid refractory, however, and require alternative therapy for which there are no standard, effective options. We have recently identified selective expression of CD52, which is targeted by alemtuzumab, by different subtypes of human dendritic cells (DCs). Monocyte-derived DCs (moDCs) express CD52, whereas Langerhans cells (LCs) and dermalinterstitial DCs (DDC-IDCs) never express this epitope, either as resident populations in normal or inflamed tissue, or as cytokine generated progeny of CD34+ HPCs in vitro. Although alemtuzumab given pretransplant eliminates host moDCs without impairing engraftment of donor moDCs, the effect of alemtuzumab given after transplant on donor moDCs is not known. MoDCs are the most highly phagocytic DCs and thereby most capable of taking up host Ags from dying cells for cross-presentation to engrafting donor T cells. The beneficial effect of antJ-CD52 therapy on GvHD may therefore derive not only from its depletion of alloactivated T cells but also from the selective elimination of moDCs from the inflammatory environment of GvHD. The preservation of LCs and DDC-IDCs after anti-CD52 treatment may allow these DCs to play formative roles in the redevelopment of acquired and beneficial immunity. This is distinct from the outcome after daclizumab (anti-CD25) or thymoglobulin/ATG therapy, both of which nonselectivelv target most or all monocytes and DCs. as well as T cells. We propose that GvHD is separable from graft-host tolerance, reconstitution of cellular immunity, and GvT benefits of allogeneic HSCT, all at the level of antigen-presentation by DCs. We will (1) determine the efficacy of alemtuzumab to achieve responses in steroid-refractory acute GvHD by its selective targeting of moDCs as well as T cells: (2) assess whether alemtuzumab exerts a steroid-sparing effect, obviates the need for other salvage therapies, lessens the incidence of chronic GvHD, and improves OS and DFS; and (3) quantify circulating levels of inflammatory cytokines in GvHD sera/plasma that may in turn support DC activation and stimulation of donor T cells against host alloantigens; and enumerate changes in circulating NK, NKT, and T-reg cells, as well as circulating and tissue-resident CD52 pos/neg DC populations. We predict that alemtuzumab will effectively manage steroid-refractory acute GvHD, preserving freedom from relapse and allowing immune reconstitution to proceed more normally in the absence of continued immune suppression by high dose steroids.