Nivolumab with peptide vaccine in patients naive to or that failed ipilimumab
Dr Jeffrey Weber - Moffitt Cancer Center, Tampa, USA
Jeffry, good to see you stepping into the ecancer studio here at ASCO and you have been talking about nivolumab and this whole thing about checkpoint inhibition, releasing the body’s ability to fight cancer. What it is that you’ve been doing in this study which also involved a vaccine?
What we did was we took groups of patients either who had never seen ipilimumab, which is the approved checkpoint protein inhibitory antibody, or we took patients who had failed or been refractory to that drug, the ipilimumab, and treated them with nivolumab with a vaccine. Why a vaccine? This particular vaccine was peptides, fragments of antigens expressed on melanoma cells but we included it as an immunologic monitoring tool. We really didn’t think it was going to cause the tumours to regress; we did it so we could measure things in the blood or even on the tumour that we could use as biomarkers.
OK, now nivolumab is a bit like ipilimumab is it?
It’s a little bit like it, it’s also a fully human antibody but it blocks a different brake on the immune system.
And the whole idea is to free up the body to fight the cancer?
That’s correct. Remember, in a car you have a couple of redundant brakes, you have a parking brake and a regular brake; the immune cells have multiple brakes, they must have six, seven or eight brakes and six, seven or eight accelerators which makes sense, you want to have a finely tuned immune system, you don’t want to develop autoimmunity, right? But in cancer there’s over-expression, too much expression of the brake and not enough of the accelerator so the T-cells are called exhausted, that’s the immunologic term which means they’re there, they’re not dead, they just don’t work.
What happened in your study, in fact?
In our study we found that you could achieve a significant response rate and get tumour shrinkage of pretty long duration whether the patients had previously seen ipilimumab or whether they had been refractory to it. So that was what was new and you did not recapitulate the side effects of ipilimumab when you gave the PD1. We also found the PD1, whether it was in the ipilimumab naïve or the ipilimumab refractory patients, was well tolerated; the responses were there and they were of long duration.
And you’re beginning to suggest the idea of sequential treatment are you?
Sequential treatment is something we will test. Steve Hodi and I from Dana Farber will test that in the next coming months of either ipilimumab-nivolumab or nivolumab-ipilimumab to see which is better. There was today, of course, a presentation by Jedd Wolchok showing that you can also give the drugs simultaneously, albeit with a fair bit of immune toxicity, and have very high response rates. We’re going to see whether you could, say, give nivolumab first then give ipilimumab after your first induction of nivolumab and also achieve a really high response rate.
So what are the clinical implications coming out of this at the moment?
The implications are you have an active drug in melanoma and not only is it active, does it induce responses that are of long duration. And you may even be able to cure some patients. I hesitate to use the c word in melanoma but maybe that’s the case.
In fact things really do seem to have been turned around a little bit in melanoma, don’t they?
Compared to ten years ago when the average melanoma doc was wandering in the wilderness, it’s a much more optimistic scenario for the patients, for the docs, for everybody.
And how does all of this fit in with the surgery and margins of excision and all of that treatment of melanoma?
The irony is it will probably give more business to the surgeons because a lot of patients are debulked with some of these drugs and rendered nearly free of disease and it may be that the surgeon can come in and complete the job and at the end they’ll be in complete remission.
Like a sort of neoadjuvant therapy.
Almost like a neoadjuvant therapy, that’s exactly correct.
How would you sum up all of this very exciting area and one of the cancers here at ASCO that we’ve seen turning round? How would you sum that up for busy cancer doctors?
Well I could say it in four words: the best is… or five words: the best is yet to come, as in the Frank Sinatra song. No, I think that this shows that immunotherapy is here to stay, it’s active, patients will clearly benefit. It’s a drug that’s active not only in melanoma but in epithelial cancers like non-small cell lung cancer and you’ll see new antibodies coming along, maybe one per year, that will continue to boost the activity of the immune system and benefit patients.
And your strategy for your patient with advanced melanoma right now should be what?
The strategy, the big decision in our field, is if you a BRAF mutated patient, do you do immunotherapy first or do you do BRAF inhibitor therapy first? That’s a big question that will have to be settled by, as always, a large trial. But it’s a great position to be in to have a plethora of drugs to choose from. So patients are now in first, second, third, fourth line treatment. It’s great.
Jeffrey, thanks for giving us your wisdom here. It’s great to see you and we look forward to more developments.