胞壁酰二肽-抗CD10复合物免疫导向治疗儿童急性B淋巴细胞性白血病微小残留病

Acute lymphoblastic leukemia (ALL) is the most frequent malignancy of childhood. The use of modern intensive induction chemotherapies results in a event-free survival (EFS) rate of 70% of B-ALL, yet 30% of ALL died of relapse. Growing evidence has suggested that minimal residual disease of leukemia (MRD) forms the basis for cancer relapse and progression, and that cytoreductive agents incompletely eradicate MRD. The therapy targeting tumor cells using monoclonal antibodies (MAb) is a potentially useful approach for antitumor therapy and has been used in some malignancies.On the basis of the role of targeted therapy and DC-based immunotherapy, the new immunomodulator by coupling anti-CD10 MAb and MDP was synthesized in the present study, the bioactivity of the new immunoconjugate was only examined to determine that anti-CD10 MAb and MDP in the new immunoconjugate still kept their own bioactivity. Peripheral blood monocyte cells from pre-B-ALL children were used as an experimental model to examine the effect of the new immunoconjugate-induced dendritic cells on anti-leuekemia of T lymphocyte. The xenograft model of leukemia and minimal residual disease in nude mice was established to examine the mechanisms that the compound played the specific immunofunction in vivo by use of the radioimmunology and living body imaging techniques.

儿童白血病是可治愈疾病，化疗可使70%以上急性B淋巴细胞性白血病(B-ALL)患儿长期无病生存,但约30%患儿死于复发。微小残留病(MRD)是复发根源,清除MRD是预防复发提高治愈率关键。单纯化疗不能清除MRD,需靠机体免疫功能。因白血病患儿对其肿瘤细胞缺乏特异性免疫应答,故自身不能清除MRD。根据卡介苗接种后,机体可对结核杆菌产生T细胞介导的特异性免疫应答及单克隆抗体免疫导向的特点，本研究将卡介苗有效成分胞壁酰二肽（MDP）与B-ALL单克隆抗体(抗CD10抗体)偶联,制备MDP-抗CD10复合物,提取B-ALL患儿的外周血免疫活性细胞与复合物、B-ALL细胞体外共同培养,检测MDP-抗CD10介导树突状细胞对T细胞杀伤B-ALL细胞作用；建立白血病及微小残留病动物模型,通过抗CD10的免疫导向,利用放免及活体成像技术研究复合物在B-ALL细胞周围产生的特异性免疫应答及对肿瘤细胞的杀伤。

微小残留病细胞(MRD)是复发根源,清除MRD是预防复发提高治愈率关键。单纯化疗不能清除MRD,需靠机体免疫功能。而白血病患儿对其肿瘤细胞缺乏特异性免疫应答,故自身不能清除MRD。既往研究主要采用单一的免疫调节制剂，缺乏靶向特点。本研究根据卡介苗接种后,机体可对结核杆菌产生T细胞介导的特异性免疫应答及单克隆抗体免疫导向的特点，将卡介苗有效成分胞壁酰二肽（MDP）与B-ALL单克隆抗体(抗CD10抗体)偶联,制备MDP-抗CD10复合物,提取B-ALL患儿的外周血免疫活性细胞与复合物、B-ALL细胞体外共同培养,检测MDP-抗CD10介导树突状细胞对T细胞杀伤B-ALL细胞作用；建立白血病及微小残留病动物模型,通过抗CD10的免疫导向,研究复合物体内靶向作用以及对肿瘤细胞的杀伤。