T-VEC is actually the only virus that is currently FDA approved for the treatment of cancer. People have been looking at viruses and other biological agents to treat cancer for more than a hundred years and viruses in particular have been looked at also for more than a hundred years given a number of different ways. But really this took off in the last several decades with the idea of both systemically giving people viruses as well as injecting them directly into tumours.
Now, originally, viral therapy in the original trials that I ran, for example with adenoviruses one called ONYX-015, and there are a number of different adenoviruses, the idea is that the virus would preferentially kill the tumour and these are oncolytic viruses. Now, it turns out that like most of the things that we thought we were doing in cancer, that the immune system probably plays a great part. For example, chemotherapy probably activating the immune system plays a huge part. The benefits of viral therapy are probably not from being oncolytic, by killing the cancer cells throughout the body like we had originally hoped, but by generating an immune response.
So T-VEC or talimogene laherparepvec is a modified herpes virus that the modifications are, one, to reduce neurovirulence. The herpes virus can be a terrible thing, we want to make certain that patients aren’t injured by giving this. It turns out that by doing that you also improve cancer specificity, in other words infecting the cancer cells. The other part is, and part of this generation of therapeutic oncolytic viruses, are that GM-CSF, which is a pro-immune cytokine, is also encoded. So the idea was not only do you get the immune effects of the virus itself but also perhaps by the gene therapy that’s encoded.
Now, our immune system, of course, is not designed to fight cancers and, in fact, our ancestors were dead probably long before most of them ended up getting cancer. However, it is highly attuned to make certain that you don’t die of bacterial and, in particular, viral infections. So therefore when you have an infection, whether it’s bacterial, and there a number of probably not as far along but the original Coley’s toxins and things like that were against bacteria, but then also large parts of the immune system are actually to make certain that we don’t die of pandemics, of viral pandemics. So therefore the idea is to recognise the invader.
Now, there are two parts to this, there’s the innate immune system which recognises patterns, either from damaged tissue or from the invaders alone, whether they’re bacteria or whether they’re viruses, and basically sets up the innate immune response which primes the immune response to something that gives both an immediate response so that you don’t die immediately of infection but it also basically passes the ball to your adaptive immune response to set up a more effective and longer-lasting immune response. What we’re trying to do is to use this basically to let your body identify the cancer as foreign and to have an immune response. There are a number of different ways that you can do this. For example, there is a huge amount of research looking at anti-cancer vaccinations. But the problem is, and I’m actually running some of those studies, is that you have to identify those epitopes that are immunogenic, that are different, so you have to sequence, some of them are off the shelf but generally you have to sequence, and you have to make up the vaccine and you have to hope that you end up getting an immune response.
So there are a number of different ways, including injecting the tumour, that you flood the zone. What you try to do is that you ended up getting tumour death, the virus infects, there’s an intense immune response hopefully, and it may vary from person to person, that some of the immune response that you have will be against the cancer itself. You really don’t care if you get a response against the virus because that’s not something you continue to get, what you want is a cancer-specific response.
What was the aim of the study you presented at ASCO this year?
T-VEC has already been shown to be effective and is actually FDA approved in the United States against melanoma. So right about the time that the checkpoint inhibitors were being developed, which really have to do with the second part, the adaptive immune response, and making certain, basically unleashing some of the things and blocking some of the things that tumours use to block that response, is that right about that same time T-VEC was being developed and injected directly into melanoma. Melanoma is a great model for a lot of things, it is really the model for the immunotherapy of cancer. The other thing is that it tends to be superficial so injecting things directly into melanomas is a relatively easy way because they are cutaneous, they’re on the skin, you can inject directly into it. So T-VEC was developed and shown that even as a single agent to have benefit, to have a response, though this was lost a little bit because of the amazing responses that were being seen at the same time initially with CTLA-4, anti-CTLA-4 antibodies, and then anti-PD1 and anti-PD-L1 antibodies which are extremely effective in melanoma but unfortunately not as effective in general, outside of some special cases, in the more common solid tumours other than lung cancer. But what I do in GI cancer, particularly colon cancer, other than patients with microsatellite instability colon cancer, which is a small minority of colon cancer, those respond great to checkpoint inhibitors. But the vast majority of people with metastatic disease, about 96-97% of microsatellite stable disease, checkpoint inhibitors by themselves do not work.
So, one of the things that we were looking for in this study, so to tee this up, was that on the one hand you have diseases that by themselves checkpoint inhibitors are really not that effective. The second thing is that these diseases tend to metastasise to the liver. So one of the reasons that we put this trial together, and this has been a relatively long gestation, one of the reasons I proposed this study, was to look at the combination. At the same time that this was being developed my colleague at UCLA who really is a world leader in this, Tony Ribas, actually published a study, a small study, in melanoma showing an extremely high response rate with the combination of a checkpoint inhibitor plus T-VEC in melanoma.
So the idea is basically trying to get checkpoint inhibitor resistant tumours, not that melanoma is all cured and there are certainly patients who don’t respond to checkpoint inhibitors, but particularly ones that have a very low percentage, and to see, one, technically can we inject where the tumours are, which frequently is in the liver. The second thing is is it safe, so technically can you do it, is it safe to do this. There actually is a literature of injecting oncolytic viruses into the liver and generally it has been safe. And do you see any responses when you combine with checkpoint inhibitors. So that was the set-up of the trial.
What did you from the study?
The things that we saw were, first of all, one of the things that you could see was that it was safe. The toxicities that we saw are what you see with viral therapy – you can see fevers and chills. We tried specifically to make certain that patients had low tumour burden because if you had inflammation of the tumour you could have inflammation of the surrounding liver and end up pushing someone over the edge. So first do no harm. But in general it was very well tolerated and technically we were able to show that sites across the world were able to have a very standardised way of injecting. In fact, we put together standardised protocols that have now been used in other, because there are other injectable agents, that either other viruses or other innate immune stimulators, such as STING agonist, TLR9 and similar. So, one, it’s definitely doable.
The other question is is it safe and the answer is yes. We did have one patient who had some cholestasis, probably due to the tumour. I think it’s really important for future development to make certain that you’re careful with how you inject and patient selection.
The other question is was it helpful. Now, there were two cohorts that we put together. In general there were three cohorts but two groups. One was patients with primary liver cancer, so hepatocellular carcinoma. That has been a real field of excitement, in fact my colleague at UCLA, Richard Finn, just published in The New England Journal and presented combination data with immune checkpoint inhibitors and other agents and this tumour is clearly sensitive to checkpoint inhibitors but, once again, not all patients. The other reason we separated it out was because, by definition, patients who have hepatocellular carcinoma have a sick liver. Virtually all of them have cirrhosis. The idea was that if they had significant toxicity it would be hard to tell whether or not that would be the same as, let’s say, someone who had colon cancer with liver metastases where the rest of the liver is actually healthy. That has not accrued as rapidly because there are so many other immune studies going on, that has been safe.
From a phase I trial, as Dan Van Hoff, one of my mentors, all of our mentors, a mentor to all of us who do drug development, said is really to look at dosing and look at safety but you sure like to see responses and it makes you feel better. One of the things that is encouraging is that we did see a response in a patient with microsatellite stable, in other words not a lot of mutations, colorectal cancer. Those patients in general you would not expect to see a response with a PD1 like pembrolizumab. So this has actually led to an expansion and the expansion is looking at other diseases including hormone receptor positive breast cancer, colorectal cancer is actually being expanded. Actually I will tell you exactly which are the other ones: triple negative breast cancer with PD-1 which is clearly an unmet need, where PD-1, actually PD-L1 but also PD-1, has shown activity. Certain other non-melanoma skin cancers. So I think that these larger studies will help show that this is both safe and hopefully has some efficacy.
The other thing that I think is also particularly interesting for the development of a combination of injectable immune stimulants, whether they’re viruses or other non-virus agents such as, as I said, TLR9 or STING agonists, is that the liver may or may not be the best place to go. It’s certainly the biggest place and it’s easy for an interventional radiologist but there may be areas that may also be more immunologically safe and also more effective such as lymph nodes. Now one of the problems is that lymph nodes tend to run along vessels but I think that we’re going to be expanding and going beyond the liver. We’ve shown this is safe, we have shown there is some preliminary evidence of efficacy in diseases that you would not expect to benefit just from a checkpoint inhibitor alone. The goal is to help people with cancer.