We were working together to see why some chronic hepatitis B carriers would develop into cirrhosis followed by cancer, which is liver cancer while some we know are doing very fine without any problems or some may have some cirrhosis but not with any cancer. So we now know that there are several factors which are associated with the development of cancer. For example, the sex – unfortunately men, if you are a hepatitis B carrier you have a higher risk than a woman. Also we know age – when you have a longer time, say by the time of 60, 70, of cirrhotic damage to the liver you have a higher chance of development of liver cancer. We also know that the viral load, because hepatitis B is a DNA virus, so we can easily measure the HBV DNA level in the plasma. When it’s higher we also know that a high viral load is also associated with the development of liver cancer. The last and probably the most significant is unfortunately if you already have evidence of cirrhosis, like the ultrasound, so that you have nodules in the liver or you have some low albumin, high bilirubin in your blood test, this is probably the most potent predictor that you are going to develop liver cancer more easily than other populations. So these are the factors we know already.
Are there any interventions?
There are two levels we can prevent the development of the liver cancer. One way is before the people get infected with hep B you can vaccinate them. In fact, the first country that implemented vaccination was Taiwan, since around the early ‘80s, so that actually now they’re already seeing a reduction in the incidence of liver cancer in adolescents or sometimes also in adults. Then, in fact, other countries like Hong Kong, Korea, Japan, also China now is also implementing whole population vaccination if you are not a hep B carrier. So actually this is a very effective way of so-called preventing infection then you can prevent the cancer.
Another way if you’re unfortunate, you’re a hep B carrier, in fact we now have a very effective drug, we call it some analogue [?] which can suppress the replication of the virus. It’s just a tablet, then you can suppress the viral load and actually there have been many data showing that you can avoid developing cancer by taking this drug. So these are two ways we can help people from a more global point of view.
What have you found in terms of new biomarkers?
Actually, interestingly, the most classical one I’m sure many doctors or even laymen would know is alpha-fetoprotein. We know that alpha-fetoprotein is associated with liver cancers, it’s elevated around 60-70%. So actually some data suggests that if you have elevated AFP during the hep B infection probably you need to undergo further investigation i.e. we call it a screening tool. In fact this is frequently done in Hong Kong as well because it’s relatively cheap – you just take blood and then you can screen out, say, whether you’re high risk or low risk. Of course, mind you, it’s not a 100% good marker – some people may not have elevation of AFP this is why we also advise those people with hep B carrier infection to undergo ultrasound regularly, every 6-12 months, so that if you develop some new nodules in the liver then you would know. Probably now we understand it’s a combination of these two things, AFP and ultrasound, which can help you screen out the early HCC, the liver cancer, for early treatment.
Another marker that we’re already interested, as I mentioned in the talk, is interleukin-10. We know it’s one of the very immuno-suppressive cytokines and when the liver cancer patients have elevated IL-10 it’s really a bad thing, as you can see in the survival curves. Basically you will die within one year’s time. So I think it’s the hallmark of immuno-suppression that in this population it’s probably good for us to act on some treatment so that we activate the immune system, so to treat the cancer.
Could you summarise the three combinations that you discussed in your presentation?
We’re now still working on it, we don’t have a standard yet but we know what we know now, as probably previous speakers have spoken, is that PD-1, the checkpoint inhibitor, is working in a small proportion of patients. Unfortunately around 90% of people are still not benefitting from this drug so we need some adding, some new drug, probably some drug with more synergistic action. I think the first combination is the immune-immune combination. For example as I mentioned, the OX40 agonist, this drug really is gas on the pedal that boosts up the immune system; together with the checkpoint inhibitors there’s a lot of data suggesting that you can downregulate the interleukin-10 you can improve the immuno-suppressive phenotype to a more immuno-dominant so that you can kill the tumour cells in the liver. Another combination is about the immune plus more conventional, we call it signalling targeted agents like the targeted therapy. One drug that I always think is useful is the VEGF, vascular endothelial growth factor. We have these drugs, sorafenib, sunitinib, so that when we combine them we can have a synergistic action again, trying to improve the trafficking of T-cells in the tumour microenvironment.
The third thing, as I mentioned, probably we need some other… This is very preliminary but now the army is mainly T-lymphocytes. You can have other cells to help you like NK cells or some other doctors have said the T-lymphocytes, B-lymphocytes. We probably need a concerted effort of different cell populations from the immune system to help you treat the cancer. So these are three broad categories that the whole world of investigators should move along.
