Alemtuzumab treatment of steroid-refractory acute GvHD

描述（由申请方提供）：我们提出了一项Alemtuzumab治疗类固醇难治性急性移植物vs.异基因造血干细胞移植受者的宿主病中度至重度急性GvHD（II-IV级）发生在30-50%的匹配的相关受体和50-70%的非相关受体的未修饰的同种异体移植物，尽管标准的预防。急性GvHD也可能发生在T细胞耗竭的同种异体移植物后，特别是来自HLA不匹配和/或无关供体的同种异体移植物。II-IV级GvHD需要全身治疗，通常是高剂量的胃肠外类固醇。然而，大约60%的这些患者证明类固醇难治性，并且需要没有标准有效选择的替代疗法。 我们最近发现了不同亚型的人树突状细胞（DC）选择性表达阿仑单抗靶向的CD 52。单核细胞衍生的DC（moDC）表达CD 52，而朗格汉斯细胞（LC）和真皮间质DC（DDC-IDC）从不表达该表位，无论是作为正常或发炎组织中的常驻群体，还是作为体外CD 34 + HPC的细胞因子产生的后代。尽管移植前给予的Alemtuzumab消除了宿主moDC而不损害供体moDC的植入，但移植后给予的Alemtuzumab对供体moDC的影响尚不清楚。MoDC是最高度吞噬的DC，因此最能够从垂死细胞中摄取宿主Ag以交叉呈递给移植供体T细胞。因此，抗J-CD 52疗法对GvHD的有益作用可能不仅来源于其对同种异体活化的T细胞的消耗，而且来源于从GvHD的炎性环境中选择性消除moDC。抗CD 52治疗后LC和DDC-IDC的保存可使这些DC在获得性和有益免疫的重建中发挥形成性作用。这与达克珠单抗（抗CD 25）或胸腺球蛋白/ATG治疗后的结果不同，这两种治疗均非选择性靶向大多数或所有单核细胞和DC。以及T细胞。 我们认为GvHD与移植物-宿主耐受、细胞免疫重建和同种异体造血干细胞移植的GvT益处是分离的，所有这些都是在DC的抗原呈递水平上。我们将（1）通过选择性靶向moDC和T细胞，确定Alemtuzumab在类固醇难治性急性GvHD中实现缓解的疗效：（2）评估Alemtuzumab是否发挥类固醇节省效应，避免其他挽救治疗的需要，降低慢性GvHD的发生率，并改善OS和DFS;和（3）定量GvHD血清/血浆中炎性细胞因子的循环水平，所述炎性细胞因子又可支持DC活化和刺激供体T细胞对抗宿主同种异体抗原;并计数循环NK、NKT和T-reg细胞以及循环和组织驻留CD 52阳性/阴性DC群体的变化。我们预测，Alemtuzumab将有效管理类固醇难治性急性GvHD，避免复发，并允许免疫重建在不存在高剂量类固醇持续免疫抑制的情况下更正常地进行。

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.