Cancer Gene Therapy Group, Molecular Cancer Biology Program and Haartman Institute and Transplantation Laboratory and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
Cancer Gene Ther. 2011 Apr;18(4):288-96. doi: 10.1038/cgt.2010.79. Epub 2010 Dec 24.
Oncolytic adenoviruses have been safe in clinical trials but the efficacy has been mostly limited. All published trials have been performed with serotype 5 based viruses. The expression level of the Ad5 receptor CAR may be variable in advanced tumors. In contrast, the Ad3 receptor remains unclear, but is known to be abundantly expressed in most tumors. Therefore, we hypothesized that a fully serotype 3 oncolytic adenovirus might be useful for treating cancer. Patients exposed to adenoviruses develop high titers of serotype-specific neutralizing antibodies, which might compromise re-administration. Thus, having different serotype oncolytic viruses available might facilitate repeated dosing in humans. Ad3-hTERT-E1A is a fully serotype 3 oncolytic adenovirus controlled by the promoter of the catalytic domain of human telomerase. It was effective in vitro on cell lines representing seven major cancer types, although low toxicity was seen in non-malignant cells. In vivo, the virus had anti-tumor efficacy in three different animal models. Although in vitro oncolysis mediated by Ad3-hTERT-E1A and wild-type Ad3 occurred more slowly than with Ad5 or Ad5/3 (Ad3 fiber knob in Ad5) based viruses, in vivo the virus was at least as potent as controls. Anti-tumor efficacy was retained in presence of neutralizing anti-Ad5 antibodies whereas Ad5 based controls were blocked. In summary, we report generation of a non-Ad5 based oncolytic adenovirus, which might be useful for testing in cancer patients, especially in the context of high anti-Ad5 neutralizing antibodies.
溶瘤腺病毒在临床试验中是安全的，但疗效大多受到限制。所有已发表的试验都是用血清型 5 为基础的病毒进行的。Ad5 受体 CAR 的表达水平在晚期肿瘤中可能存在差异。相比之下，Ad3 受体的表达情况尚不清楚，但已知在大多数肿瘤中大量表达。因此，我们假设完全基于血清型 3 的溶瘤腺病毒可能对治疗癌症有用。接触过腺病毒的患者会产生高水平的血清型特异性中和抗体，这可能会影响再次给药。因此，拥有不同血清型的溶瘤病毒可能会促进人类的重复给药。Ad3-hTERT-E1A 是一种完全基于血清型 3 的溶瘤腺病毒，由人端粒酶催化结构域的启动子控制。它在代表七种主要癌症类型的细胞系中具有体外疗效，尽管在非恶性细胞中观察到低毒性。在体内，该病毒在三种不同的动物模型中具有抗肿瘤功效。虽然 Ad3-hTERT-E1A 和野生型 Ad3 介导的体外溶瘤作用比 Ad5 或 Ad5/3（Ad5 中的 Ad3 纤维扣）为基础的病毒慢，但在体内，该病毒的效力至少与对照相当。在存在中和抗 Ad5 抗体的情况下保留了抗肿瘤功效，而基于 Ad5 的对照则被阻断。总之，我们报告了一种非 Ad5 基的溶瘤腺病毒的产生，该病毒可能对癌症患者的测试有用，尤其是在存在高抗 Ad5 中和抗体的情况下。
