CANCER THERAPY USING ANTIBODY-MEDIATED DELIVERY OF ONCOLYTIC VIRUSES

一些感染人类的病毒目前正在研究用于治疗癌症;这些病毒被称为溶瘤病毒。这些溶瘤病毒中的一些很少在人类中产生严重症状，而另一些已经被修改，使它们不再引起疾病。它们既可以直接杀死癌细胞，也可以刺激人体自身的免疫系统攻击癌症。然而，关于溶瘤病毒，免疫系统代表一把双刃剑，因为除了刺激抗癌免疫应答之外，溶瘤病毒还刺激抗病毒免疫应答，包括产生抗病毒中和抗体。目前的看法是，这些抗病毒中和抗体是静脉内递送溶瘤病毒的屏障，因为它们将中和病毒并防止其到达肿瘤。因此，重复静脉注射将是无效的，因为抗病毒免疫反应是在第一次给药后产生的。然而，我们的研究意外地发现中和抗体可能在癌症治疗中发挥作用。我们发现血液中的一些称为单核细胞的免疫细胞可以装载预先形成的病毒-抗体复合物（因此病毒被完全中和），然后通过目前未知的机制重新激活病毒，使其可以转移到肿瘤细胞，从而感染并杀死肿瘤细胞。这是非常出乎意料的，因为单核细胞被认为会破坏它们遇到的所有抗体包被的病毒。因此，我们的研究对未来的溶瘤病毒疗法和临床溶瘤病毒疗法治疗策略的设计具有重要意义，我们建议进一步研究这一点，以确定有多少溶瘤病毒目前正在调查中的临床，可以重新激活单核细胞以这种方式。我们还将发现血液中的其他细胞是否也可以像单核细胞一样重新激活抗体中和的病毒，并研究该过程中涉及的机制。这项工作将增加我们对中和抗体在溶瘤病毒治疗中的作用的理解，并使溶瘤病毒用于治疗癌症的使用得到改进。

Some viruses that infect humans are currently under investigation for the treatment of cancer; these are referred to as oncolytic viruses. Some of these oncolytic viruses rarely produce serious symptoms in humans while others have been modified so that they no longer cause disease. They act both by directly killing cancer cells and also by stimulating the body's own immune system to attack the cancer. However, with regard to oncolytic viruses, the immune system represents a double-edged sword, because as well as stimulating anti-cancer immune responses, oncolytic viruses also stimulate anti-viral immune responses, including the production of anti-viral neutralizing antibodies. The current perception is that these anti-viral neutralizing antibodies are a barrier to intravenous delivery of oncolytic viruses, because they will neutralize the virus and prevent it reaching the tumour. Thus repeated intravenous injections would be ineffective because of the anti-viral immune response that is generated after the first dose is given to a patient. However, our research has unexpectedly found that neutralizing antibodies may play a role in cancer treatment.We have found that some immune cells in the blood called monocytes can be loaded with pre-formed virus-antibody complexes (so the virus is fully neutralized) and then, by mechanisms not currently known, reactivate the virus so that it can be transferred to tumour cells which it infects and kills. This is very unexpected, as monocytes are thought to destroy all antibody-coated virus they encounter. Our research therefore has significant implications for the future of oncolytic virotherapy and for the design of clinical oncolytic virotherapy treatment strategies.We propose to investigate this further to determine how many of the oncolytic viruses currently under investigation in the clinic, can be reactivated by monocytes in this way. We will also find out whether other cells in the blood can also reactivate antibody-neutralized viruses in the same way as monocytes and investigate the mechanisms involved in the process. This work will increase our understanding of the role of neutralizing antibodies in oncolytic virotherapy and enable improvements in the use of oncolytic viruses for treating cancer.