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Clinical study of LAK adoptive immunotherapy for angiosarcoma enhanced by anti-angiosarcoma × anti-CD3 bispecific antibody

抗血管肉瘤×抗CD3双特异性抗体增强LAK过继免疫治疗血管肉瘤的临床研究

基本信息

批准号：
12670833
负责人：
MASUZAWA Mikio
金额：
$ 1.66万
依托单位：
KITASATO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

LAK adoptive immunotherapy is effective in the treatment of angiosarcoma. To enhance the effect of this immunotherapy, we devised the utility of a bispecific antibody (BSAb) to crosslink between tumor cells and LAK cells. We established an anti-angiosarcoma specific monoclonal antibody HEW-3 using a human angiosarcoma cell line ISO-HAS as an immunogen (Int. J. Cancer 81 : 305-308, 1999). HEW-3 was an IgM antibody and recognizes a 43 Kd molecule in the immunogen. The BSAb was made from the respective F(ab') _2 regions of HEW-3 for angiosarcoma cell and anti-CD3 antibody for LAK cell. The BSAb enhanced LAK cytotoxicity against ISO-HAS cells in a dose- and time-dependent manner. Moreover, the cytotoxic activity was related to a dose of TNFα measured in the supernates in vitro. The in vivo effect of the BSAb in LAK immunotherapy was studied in a human angiosarcoma SCID mouse model (WB-SCID) established by us (J. Dermatol. Sci. 27 : 88-94, 2001). The growing angiosarcoma was suppressed significantly only by initial 4-times intra-lesional injection of the BSAb immunotherapy in comparison with LAK immunotherapy alone. Based on these basic results, we treated three patients with angiosarcoma by this therapy. The 2.5μg BSAb combined with LAK cells was administered to two patients with angiosarcoma of the scalp by intra-lesional injection, and the 15 μg BSAb combined with LAK cells to one patient with intracranial angiosarcoma by selective intra-arterial injection. The increase in the human anti-mouse antibody prevented continuous administration, but we detected the clinical exact but temporal effect of this immunotherapy in each patient. Side effects in this immunotherapy were only fever in one patient and CRP elevation in two patients without visceral damage. This prospective study could promote the making of human-type BSAb for LAK immunotherapy of angiosarcoma in the near future.

LAK过继免疫治疗是治疗血管肉瘤的有效方法。为了增强这种免疫治疗的效果，我们设计了一种双特异性抗体（BSAb）的效用，以交联肿瘤细胞和LAK细胞之间。我们使用人血管肉瘤细胞系ISO-HAS作为免疫原建立了抗血管肉瘤特异性单克隆抗体HEW-3（Int. J. Cancer 81：305-308，1999）。HEW-3是IgM抗体，识别免疫原中的43 Kd分子。分别用HEW-3的F（ab '）_2区和LAK细胞的抗CD_3抗体制备BSAb。BSAb可增强LAK细胞对ISO-HAS细胞的杀伤作用，并呈剂量和时间依赖性。此外，细胞毒活性与体外上清液中测得的TNFα剂量相关。在我们建立的人血管肉瘤SCID小鼠模型（WB-SCID）中研究了BSAb在LAK免疫治疗中的体内作用（J. Dermatol. Sci. 27：88-94，2001）。与单独的LAK免疫治疗相比，仅通过最初的4次病灶内注射BSAb免疫治疗显著抑制生长的血管肉瘤。基于这些基本结果，我们用这种疗法治疗了三例血管肉瘤。对2例头皮血管肉瘤患者行2.5μ gBSAb联合LAK细胞瘤内注射，1例颅内血管肉瘤患者行15 μ gBSAb联合LAK细胞瘤内选择性动脉注射。人抗小鼠抗体的增加阻止了连续给药，但我们在每个患者中检测到了这种免疫疗法的临床确切但短暂的效果。这种免疫疗法的副作用仅为1例患者发热，2例患者CRP升高，无内脏损伤。该前瞻性研究为进一步研制人源性BSAb用于血管肉瘤的LAK免疫治疗奠定了基础。