3rd Immunotherapy of Cancer Conference (ITOC3)
Combination of viroimmunotherapy with checkpoint inhibitors
Prof Alan Melcher - The Institute of Cancer Research and The Royal Marsden Hospital, London, UK
I’m a clinician scientist who has been interested in immunology and the immunotherapy of cancer for many years but my particular interest is in oncolytic viruses which are anti-cancer viruses which were initially developed as agents to directly infect, replicate, lyse and kill cancer cells. That’s why they’re called oncolytic, very much about direct killing. But what we’ve found now over the last five years or so, and not only our group but many others around the world, is actually how these agents work is more by stimulating the immune system to attack the cancer rather than the virus directly killing the cancer cells itself. So, in a sense, oncolytic viruses now are really forming part of the world of immunotherapy which is why we’re talking at this conference and, I think, are increasingly recognised as such.
Does this serve as a red flag to the host immune system?
Exactly, so because cancers do many things to avoid immune recognition and destruction they escape from immune surveillance and continue to grow. Of course our immune system is extremely well evolved to recognise viruses so if you can actually get a virus into the tumour an immune system that was otherwise asleep will wake up and potentially attack. That’s how and why we feel these agents are really, and some people are calling them, viroimmunotherapy or even oncolytic immunotherapy.
How does the combining of viroimmunotherapy and checkpoint inhibitors actually work?
What has happened in the world of virotherapy is one agent has now been licensed called talimogene laherparepvec which is a herpes virus encoding GM-CSF owned by Amgen. That has taken the field a significant step forward; there was a large randomised trial which showed some evidence of efficacy with that virus given by intratumoural injection into patients with advanced melanoma. However, the responses were not great and, as is always the way with oncology in general, people wanted to and looked to combine things. So there are now trials going on combining that particular virus, the Amgen virus, with checkpoint inhibitor.
But what we’ve been particularly interested in is looking at, if you like, a rationale behind combining checkpoint inhibition with virotherapy rather than just empirically putting two things together because two is better than one. So what I’ll talk about at the meeting, and in my talk in particular, is we’ve focussed on a different oncolytic virus called reovirus. We’ve now down some biological endpoint clinical trials where we’ve shown that intravenous delivery of that virus, which is a far more practical way of using the agent than direct intratumoural injection, can work in patients. So we’ve done two so-called window of opportunity studies where we’ve taken patients with cancer planned for surgery, given them intravenous virus before that operation and been able to look in the tumour to see whether the virus was delivered, which it was, but also able to look in the tumour and the blood for signs of immune activation. The particular focus of talking at this meeting is about our most recent trial in brain tumours where once again we showed that we can give intravenous reovirus to patients before surgery for brain tumours and show that the virus does indeed gain access into the tumour. That was entirely uncertain and most of the trials that go on are direct intratumoural injection in brain tumours because the worry is either the virus will get neutralised in the blood or it wouldn’t get across the blood-brain barrier. But we found in patients that indeed it does.
Then following on from that in terms of getting to the question of checkpoint inhibitors, we were also able to show in the patients treated in this way that in particular there was upregulation of PD-L1 within the tumours in patients treated with reovirus relative to patients who weren’t in the trial. So viruses, and we’ve found this in other contexts as well, can upregulate these checkpoint molecules and that provides a rationale for combining virotherapy with checkpoint inhibitor therapy. So we took that data from the clinic back into mouse models again and indeed have now shown in a couple of different systems, both within and without the brain, that combination of reovirus therapy with anti-PD1 therapy improves efficacy, at least in a murine model.
On the basis of that we’re now developing two further trials going back and forth between the clinic and the laboratory which is our particular focus of interest. One where we’re adding reovirus therapy to chemoradiation after surgery for high grade glioma and the second trial, which is earlier in development, will be to give reovirus and anti-PD1 therapy to patients with recurrent glioma.
Have there been any adverse effects from the use of reprogrammed viruses?
The short answer is no and in fact I think now T-VEC has been given to hundreds of patients and actually there’s a consistent theme which I think is very important across virotherapy that the side effect profile is really very minimal. People feel rather fluey and get high temperatures sometimes for a couple of days after treatment but it settles very quickly. What that means is because the side effects are relatively few it does open the opportunity to combine with other agents including checkpoint inhibitors. So the only reported data from one abstract of the early phase I data from T-VEC plus ipilimumab has shown an encouraging response rate of nearly 50% but, most importantly at this stage, a manageable toxicity profile. So I think one of the appeals of viroimmunotherapy is that it can be combined with other agents, whether it be chemotherapy, radiotherapy or other immunotherapies.
What do you think the future holds for viroimmunotherapy?
I think it’s very exciting times in immunotherapy as a whole, there’s no question. There was a concern a little while back first it wouldn’t work but then it would only work in melanoma. It’s now quite clear that the checkpoint inhibitors work in a range of cancers. The world of viruses is still further behind but for enthusiasts like myself we hope that in five to ten years’ time the viruses may be where the checkpoint inhibitors are now. The way they are most likely to progress and advance, as I mentioned, as single agents they’re not that impressive although they have got a licence, but what is more impressive and hopeful is the combination strategies, particularly with checkpoint inhibitors. We need more trials, both early and then late stage, to do that but those are already underway and it’s going to move very quickly now.