Raykov Zahari, Grekova Svetlana, Galabov Angel S, Balboni Ginette, Koch Ute, Aprahamian Marc, Rommelaere Jean
Infection and Cancer Program, Abteilung F010 Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, D-69120, Heidelberg, Germany.
Oncol Rep. 2007 Jun;17(6):1493-9.
Oncolytic viruses have emerged as a novel class of potent anticancer agents offering an improvement on chemo- and radiotherapy in terms of tumor targeting and reduction of side-effects. Among these agents, autonomous parvoviruses have attracted the attention of researchers for their ability to preferentially replicate in and kill transformed cells, and to suppress tumors in the absence of adverse reactions in various animal models. We have previously shown that lethally irradiated autologous tumor cells can support parvovirus H-1PV production and serve as carriers to deliver progeny H-1PV into the vicinity of lung metastases in a rat tumor model, resulting in H-1PV infection of and multiplication in metastatic cells. It is known that irradiated autologous (neoplastic) cells can also act as a therapeutic vaccine against the original tumor. Yet the ability of these cells to suppress metastases in the above model was found to be much increased as a result of their H-1PV infection. This prompted us to determine whether H-1PV boosted the tumor-suppressing capacity of the autologous vaccine by increasing its immunogenic potential and/or by making it a factory of oncolytic viruses able to reach and destroy the metastases. Both effects could be dissociated in the presence of neutralising antibodies which either prevent the progeny viruses from spreading to metastatic cells, or deplete the CD8 effector cells from the immune system. This strategy revealed that the H-1PV infection of tumor cells enhanced their ability to trigger an immune response for which uninfected tumor cells could be the targets, thereby amplifying and taking over from the direct viral oncolytic activity. This dual oncolytic/vaccinal effect of H-1PV holds out promises of clinical applications to cancer therapy.
溶瘤病毒已成为一类新型强效抗癌药物，在肿瘤靶向性和副作用降低方面比化疗和放疗有所改进。在这些药物中，自主细小病毒因其能够优先在转化细胞中复制并杀死它们，以及在各种动物模型中无不良反应的情况下抑制肿瘤的能力而吸引了研究人员的关注。我们之前已经表明，经致死剂量照射的自体肿瘤细胞能够支持细小病毒H-1PV的产生，并作为载体将子代H-1PV递送至大鼠肿瘤模型中肺转移灶附近，从而导致转移细胞被H-1PV感染并增殖。已知经照射的自体（肿瘤）细胞也可作为针对原始肿瘤的治疗性疫苗。然而，在上述模型中，这些细胞抑制转移的能力因H-1PV感染而显著增强。这促使我们确定H-1PV是否通过提高其免疫原性潜力和/或使其成为能够到达并摧毁转移灶的溶瘤病毒工厂来增强自体疫苗的肿瘤抑制能力。在存在中和抗体的情况下，这两种效应可以分开，中和抗体要么阻止子代病毒扩散到转移细胞，要么从免疫系统中耗尽CD8效应细胞。该策略表明，肿瘤细胞的H-1PV感染增强了它们触发免疫反应的能力，而未感染的肿瘤细胞可能成为该免疫反应的靶标，从而放大并取代了直接的病毒溶瘤活性。H-1PV的这种双重溶瘤/疫苗效应为癌症治疗的临床应用带来了希望。
