The development of ipilimumab has demonstrated that immunotherapies can impact survival, and therapeutic vaccines such as sipuleucel-T (trade name Provenge) and PSA-TRICOM (trade name PROSTVAC) have also been shown to increase patient survival. Prof Angus Dalgleish explains how these treatments work, explains new data which suggest that affective vaccines will soon be developed for lung cancer and talks about trials that have been conducted to investigate the combination of ipilimumab with vaccines. Prof Dalgleish explains that these vaccines do not appear to be overly specific, outlines how this is likely to make them more affordable and discusses his hopes for their successful combination with other cancer therapies.
ASCO 2011 Annual Meeting, 3—7 June 2011, Chicago
Future for immunotherapies
Professor Angus Dalgleish – St George’s University, London, UK
The headlines have obviously been the success of ipilimumab which is basically an immunotherapy which has had a major impact on survival with melanoma for the first time and then couple that with the new drugs coming through and actually there is evidence that combining the two together, ipilimumab with chemotherapy and any of the other new drugs, will work better than the ipilimumab alone. But to me, this is very exciting that immunotherapy is actually finally on the map, as it were, albeit in the form of an antibody. The antibody, basically, is one that just takes the brakes off the immune system so instead of being a vaccine, it’s basically taking all the negative facts, allowing the body’s natural responses to the tumour to proliferate and we’ve got activity.
Last year we had the big breakthrough with Dendreon and the Provenge sipuleucel-T for prostate cancer, and that’s a glass ceiling in the fact that it’s the first therapeutic vaccine to get approved by the FDA. It has got limited application, I feel, because it’s very expensive to produce, it’s bespoke production, it would be very difficult to do that for all the people in the world who are eligible for it and the cost is very high, but that’s the first and it’s a glass ceiling. You’ve got other prostate vaccines coming through which look very encouraging, there’s the PROSTVAC which is the avian and cowpox one, that’s showing a really nice split. Again both of them very interesting, the survival splits are virtually identical, they’re not occurring until about twelve months and then they’re kicking in and you’re getting a survival, not the initial progression free survival we all got in the phase II studies which are done in specialised centres, as soon as you go multi-centre you seem to lose that but what it has confirmed is the overall survival. I think that one of the main reasons for this is that people who are vaccinated have their immune system boosted, they respond better to other treatments and I think this is what we’re going to see sequentially with the other solid tumour types. I’ve been most impressed here with the lung cancer, the lung cancer vaccines are going to be really big, probably next year. They’re splitting really nicely.
What does splitting really nicely mean, Angus?
With regards to survival benefit.
So tell me about this.
People who are getting vaccines, along with the chemotherapy, are getting a survival benefit and, again, it’s occurring late. It’s not occurring early, you’re not getting an early break.
So there’s no impact of the vaccine added to the chemotherapy until late?
Until late, yes.
And then the curves diverge, and that’s what you mean as splitting?
That’s what I call splitting, yes.
That’s fine, that’s quite important. So you’re dealing with a different modality and we’re learning how to understand the tempo and it’s much slower, is what you’re saying?
It is much slower.
Is that a big surprise?
No, not for those of us who have been used to repeated failure developing vaccines for quite a while.
You need to be patient and young to start in vaccine research.
Yes, you do. What is slightly surprising is the fact that they’re working at all, albeit late, after being so disappointed and not getting any early signature.
Tell me about the lung one.
The lung ones, it’s more than one technology, we’re seeing it with two or three different lung vaccines. One of the ones that has been known for a while, there’s a couple based on muc, one’s Transgene and the other is Merck. What is interesting, and this is a phenomenon we’re going to see more and more which is quite exciting, is the Transgene one wasn’t particularly significant, the split again occurs late for getting a survival advantage, but it didn’t reach significance. What they have shown is that if you exclude people who have activated NK cells at the beginning, you actually exclude those, then the survival advantage is really very significant. So we’re actually now getting into the realm of there are some people who will not benefit from the vaccine, these people need to be excluded. My own research has been focussing on that and we were looking for magic responder markers; we don’t find that but what we do find is that all the non-responders have high inflammatory markers.
And why is that?
Well cancer is an inflammatory disease, that’s my one line interpretation; it arises in inflammation and inflammation feeds it, it’s a lovely rose bed for cancers to grow on. If that inflammation is too much, one of the things you get in inflammation is marked immune suppression. I think these people, there’s too much immune suppression so you’ll only raise a bit of immune response, the activated cells come in and they’re just a wall of suppressive cytokines from the inflammation and they don’t get any benefit. So they need to have some other modality to help treat them.
So you’re looking at a completely different kind of biomarker, an immunomarker I suppose? What do you think about the possibility of combining some of these vaccines with ipilimumab?
That’s already been tried and it was interesting because they tried it in melanoma and they tried it with a vaccine, GP100, which is thought to be one of the best ones expressed in melanoma, and that was a three year wait study, an original trial. Actually what was interesting was the ipilimumab alone, although it was not significant but it did actually do slightly better than the ipilimumab with the vaccine. I have discussed this with my colleagues and some are quick to point out that they don’t think GP100 is a very good vaccine and that if they use a decent one then things might differ. Certainly in the mouse models that would appear to be the case, that you use ipilimumab to greatly boost response to vaccines.
So what are you expecting at ASCO 2012 then?
ASCO 2012, I think we will see maturing data on lung vaccines, without a doubt, and possibly the prostate ones, the prostate coming behind. I saw another one today showing a survival advantage early on, smaller numbers admittedly, but in colorectal and the colon has always been one which, to me, has always made great sense for a vaccine.
And what’s the antigen in this paper you saw?
To be quite honest, I can’t remember the actual antigen at the moment, it was just the fact that there was one there with a split. But one of the points I’d like to make which is quite interesting, is that the vaccines we’re seeing making a difference, there’s nothing too specific. You’re seeing it from dendritic cells to lung vectors with whole cells, seeing it with a whole range of different technologies in different tumour types, and that’s absolutely fascinating because for years they said it may only work in melanoma and it clearly didn’t. From my point of view it’s always the wrong one to try.
A kidney cancer or two.
You have to remember, pointing out, that the renal cancer and the colorectal cancer were the first ones in randomised studies to show clinical benefit. They were both published in The Lancet over a decade ago but they were autologous, bespoke vaccines that are always going to be very problematical, particularly colorectal with GMP and things like that.
And $90,000 a shot for your Provenge.
$90,000 a shot for Provenge. But I think that, because these things are showing that the technology is not as important as we thought, that we should be able to bring that down, and I shouldn’t be saying this if Dendreon people are listening, to a hell of lot cheaper. But the applications for the vaccine in the cancer pathway is going to be pan, it’s not instead of, it’s as well as because things work better, particularly radiotherapy. You have people who are vaccinated and you think nothing much is happening, give them radiotherapy and it’s just staggering. You get the tumour shrinks in the first few shots of the radiotherapy and you don’t see that in most patients that have not had vaccines but, once again, they’re noticing it with CTLA4. So the ipis, they’re seeing massive response to radiotherapy too.
It’s really exciting and I share your confidence for the next couple of years, a harvest of all the twenty, thirty years of effort that you’ve been putting in in the lab with frustrating negative results is now coming good. And it’s great news for patients, particularly those melanoma patients who have already got at least two options which they didn’t have even two years ago, which is terrific. Gus thank you very much indeed for coming on ecancer.tv, I appreciate it.
Thank you very much for having me.