Alemtuzumab treatment of steroid-refractory acute GvHD

阿仑单抗治疗类固醇难治性急性 GvHD

• 批准号: 6797077
• 负责人: James William Young
• 金额: $ 34.54万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6797077
• 关键词: CD antigens; CD34 molecule; Langerhans' cell; T lymphocyte; antigen presenting cell; clinical research; clinical trial phase II; cytokine; dendritic cells; drug administration rate /duration; graft versus host disease; hematopoietic stem cells; hematopoietic tissue transplantation; human subject; human therapy evaluation; hybridomas; immune tolerance /unresponsiveness; immunopathology chemotherapy; interferon alpha; interleukin 1; long term survivor; longitudinal human study; monoclonal antibody; monocyte; natural killer cells; patient oriented research; stem cell transplantation; steroids; surface antigens; tumor necrosis factor alpha

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.

描述（由申请人提供）：我们提出了一项对alemtuzumab的II期研究，用于治疗同种异体造血干细胞同种异体移植物的接受者中类固醇急性急性移植物。尽管有标准的预防，但中度至重度急性GVHD（II-IV年级）发生在30-50％的相关接受者中，未修饰的同种异体移植物的无关接受者中有50-70％发生。急性GVHD也可能发生在T细胞耗尽的同种异体移植后，尤其是来自HLA不匹配和/或不相关的供体中的急性GVHD。 II-IV级GVHD需要全身治疗，通常为高剂量的肠胃固醇。但是，这些患者中约有60％证明了类固醇难治性，并且需要替代治疗，而没有标准的，有效的选择。 我们最近已经确定了由alemtuzumab靶向的CD52的选择性表达。单核细胞衍生的DCS（MODC）表达CD52，而Langerhans细胞（LCS）和皮肤互犯DC（DDC-IDC）从不表达此表位，既可以作为正常或发炎的组织中的居民，或者是细胞因子产生的CD34+ HPC中的细胞因子产生的ecrogeny+ HPC。尽管给定前植物的Alemtuzumab消除了宿主MODC而不会损害供体MODC的植入，但是移植后对供体MODC的ALEMTUZUMAB的影响尚不清楚。 MODC是最高度吞噬的DC，因此最能够从垂死的细胞中吸收宿主AG进行交叉呈递到植入供体T细胞。因此，ANTJ-CD52治疗对GVHD的有益作用不仅可以从其同种活化的T细胞的消耗中得出，而且还取决于从GVHD的炎症环境中选择性消除MODC。抗CD52治疗后的LCS和DDC-IDC保留可能使这些DC在获得和有益的免疫力的重建中起形成性作用。这与Daclizumab（抗CD25）或胸腺球蛋白/ATG治疗后的结果不同，这两者都非核细胞大多数或所有单核细胞和DC靶向。以及T细胞。 我们建议GVHD与GRAFT-HOST耐受性，细胞免疫的重构以及同种异体HSCT的GVT益处，这都是DCS的抗原表达水平。 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; （3）量化GVHD血清/血浆中炎性细胞因子的循环水平，进而支持DC激活和刺激供体T细胞针对宿主同种抗原的刺激；并列举循环NK，NKT和T-REG细胞的变化，以及循环和组织居民CD52 POS/NEG DC种群的变化。我们预测，Alemtuzumab将有效地管理类固醇难治性的急性GVHD，从而保留了免受复发的自由，并允许在没有高剂量类固醇的持续免疫抑制的情况下更正常地进行。