Cancer Gene Therapy Group, Transplantation Laboratory, Haartman Institute and Finnish Institute of Molecular Medicine, Department of Bacteriology and Immunology, Haartman Institute, Helsinki Medical Imaging Center, University of Helsinki, Helsinki, Finland.
Cancer Res. 2010 Jun 1;70(11):4297-309. doi: 10.1158/0008-5472.CAN-09-3567. Epub 2010 May 18.
Granulocyte macrophage colony-stimulating factor (GMCSF) can mediate antitumor effects by recruiting natural killer cells and by induction of tumor-specific cytotoxic T-cells through antigen-presenting cells. Oncolytic tumor cell-killing can produce a potent costimulatory danger signal and release of tumor epitopes for antigen-presenting cell sampling. Therefore, an oncolytic adenovirus coding for GMCSF was engineered and shown to induce tumor-specific immunity in an immunocompetent syngeneic hamster model. Subsequently, 20 patients with advanced solid tumors refractory to standard therapies were treated with Ad5-D24-GMCSF. Of the 16 radiologically evaluable patients, 2 had complete responses, 1 had a minor response, and 5 had disease stabilization. Responses were frequently seen in injected and noninjected tumors. Treatment was well tolerated and resulted in the induction of both tumor-specific and virus-specific immunity as measured by ELISPOT and pentamer analysis. This is the first time that oncolytic virus-mediated antitumor immunity has been shown in humans. Ad5-D24-GMCSF is promising for further clinical testing.
粒细胞巨噬细胞集落刺激因子 (GMCSF) 通过招募自然杀伤细胞，并通过抗原呈递细胞诱导肿瘤特异性细胞毒性 T 细胞，从而发挥抗肿瘤作用。溶瘤肿瘤细胞杀伤可产生有效的共刺激危险信号，并释放肿瘤表位供抗原呈递细胞取样。因此，设计并构建了一种编码 GMCSF 的溶瘤腺病毒，并在免疫功能正常的同种异体仓鼠模型中显示出诱导肿瘤特异性免疫的能力。随后，20 名对标准治疗耐药的晚期实体瘤患者接受了 Ad5-D24-GMCSF 治疗。16 名可进行影像学评估的患者中，2 名完全缓解，1 名部分缓解，5 名疾病稳定。在注射和未注射的肿瘤中均频繁观察到应答。治疗耐受性良好，并通过 ELISPOT 和五聚体分析检测到诱导了肿瘤特异性和病毒特异性免疫。这是首次在人类中显示溶瘤病毒介导的抗肿瘤免疫。Ad5-D24-GMCSF 具有进一步临床测试的潜力。
