癌症的靶向基因 - 痘苗溶瘤病毒治疗策略

The mortality of cancer was about 7.8 million each year worldwide and about 1.9 million in China. Of course, it is a key problem worldwide. The idea (or strategy) of Cancer Targeting Gene-Viro-Therapy (CTGVT) was initiated by professor Xin-Yuan Liu in 2001. The principle of construction is to insert an antitumor gene into the oncolytic virus (OV). Therfore the CTGVT is actually an OV-gene therapy which combines the advantage of both gene therapy and oncolytic virus therapy. The resulting CTGVT (OV-gene) is not 1+1=2, and is 1+1=10-100. We insist to study it from 2001 till date (2013) for twelve years and have published about 90 (not bad IF value) papers. We have accumulated enough experiences in the studying of CTGVT by the use of CTGVT-DG strategy i.e. the Double Genes Strategy which could completely eliminate all the inoculated tumor since two genes may have synergetic or compensatory effect. In 2011, there are two events occurred: 1. The famous Amgen Inc. paid 1 billion USD to purchase an OV-gene product, OncoHSV-GM-CSF (OV from HSV); 2. The OncoPox-GM-CSF (OV from Poxviurs) was published in Nature. This two events greatly elevate the reputation of CTGVT (OV-gene) strategy. The oncolytic virus (OV) used in our past work is OncoAd (OV from adenovirus) which can not be administrated by i.v. but by intratumor injection, since the blood system will eliminate the OncoAd whereas the OncoPox could not. Therefore we change vector used in our lab from OncoAd to OncoPox since late 2011. By the combined use with our double gene strategy, our products of OncoPox-gene1-gene2 will be sure to have much higher antitumor effect than that of Nature or 1 billion USD products.

癌症全球年死亡约780万人，中国约190万人，是全球重大科学问题。我们曾创建癌症靶向基因-病毒治疗（Cancer Targeting Gene-Viro-Therapy，CTGVT）策略，其基本原理是将抗癌基因插入到溶瘤病毒（OV）中而成，故实为OV-gene，这样把癌症的基因治疗与病毒治疗结合起来了，利用双基因策略CTGVT-DG，常常可在小鼠中全歼移植性肿瘤，获重要进展。但我们过去所用溶瘤病毒载体均为OncoAd（即OV来自adenovirus），而OncoAd-gene只能用于瘤内注射，静脉注射会被血液系统消除掉，故从2011年改用OncoPox（OV来自Poxvirus）载体。也同时利用双基因的策略，以构建OncoPox-gene1-gene2，其抗癌效果将一定会超过Amgen用10亿美元购买的OncoHSV-GM-CSF以及Nature文章的产品OncoPox-GM-CSF。

溶瘤病毒（Oncolytic Virus）是目前流行的抗癌药物的一个分支，OV有一个特点是：可靶向癌症并在其中复制。这点科学界大家都是知道的，但过去无人重视，系统地利用这点制造抗癌良药，我们就是利用了这点，在其中加上一个抗癌基因，成为OV-gene。当初我们把它称为“癌症的靶向基因‐溶瘤病毒治疗”，后来就简称为“癌症的靶向基因‐病毒治疗”（Cancer Targeting Gene-Viro-Therapy, CTGVT），关于CTGVT（OV-gene）的抗癌作用，由于它利用了OV的复制作用，带动了基因的复制功能，抗癌效果增加了100倍，如果再利用OV的复制功能，再把第二个基因加到OV上变成CTGVT-DG（OncoAd-gene1-gene2或OncoAd-gene1+ OncoAd-gene2）可将移植性肿瘤全部消灭光，当然两个基因之间应该有互补作用或者是有协同效应而不是相反。此外，上述以腺病毒为载体的OncoAd可将移植性肿瘤全部消灭光，以痘病毒为载体的OncoPox则不能完全杀光，但以痘苗溶瘤病毒为载体（OncoPox）也有其优点：1.它不整合到染色体，是唯一的在胞浆中复制的病毒，故把它称为胞浆工厂病毒；2. OncoPox-gene可静脉注射（不被抗体或补体所清除），这也是OncoPox载体的很大优越性；3. Poxvirus本身就有选择性的杀伤癌细胞功能；4.对Poxvirus可以进行双缺乏再加双基因，还可进行三缺失加三个抗癌基因，故肯定可得到很好的抗癌效果；5.可插入25Kb这么大的外源gene等等，所以我们构建了很多以溶瘤痘病毒为载体的产品，如OncoPox-Trail、OncoPox-IL-24、OncoPox-MnSOD、OncoPox-IL-24-MnSOD、OncoPox-Trail-GM-CSF、OncoPox-Trail-MnSOD，并且取得极好的抗癌效果，仅OncoPox-Trail的抗癌效果就比全球最好抗癌PD-1抗体还好，比全球性大公司Amgen产品OncoHSV-GM-CSF的产品就更不在话下了。经比较，单基因以OncoPox-IL-24抗癌效果最好，它的抗癌能力就可超过Amgen的OncoPox-GM-CSF。OncoPox含单基因不如双基因好，而在双基因中又以OncoPox-IL-24-MnSOD最好，它对很多癌症能达到近1