3rd Immunotherapy of Cancer Conference (ITOC3)

Rationale for combining immunotherapy with chemotherapy

Prof Angus Dalgleish - St. Georges University, London UK

I’ve been talking today about the fact that immunotherapy needs to be combined to enhance it. This partially explains why an awful lot of vaccine trials have failed, that they were singular entities with quite difficult endpoints whereas you really need to combine immunotherapies to get the best out of them. I was just demonstrating the simplicity – you wouldn’t give a vaccine without an adjuvant, well in a therapeutic vaccine we need to give something else to either add to it and in the old days we added in a cytokine like IL-2 or we put it with a TLR agonist etc. That’s the first thing and, of course, now everybody else is talking about combining it with a checkpoint like ipi or a PD1. Then the second point I made, a very strong point, is to enhance clinical response you need to combine it with another modality. It doesn’t seem to matter what that is because all the modalities seem to enhance, whether it be radiotherapy, any form of radio-ablation, chemotherapy and there’s even endocrine therapy we didn’t discuss but there’s very good examples of that too. Then to combine all that together, that is really the minimum required to get the maximum benefit.

Then I discussed that there was a real importance to the sequentiality of how you did the combinations. There’s no doubt that some people who have been primed as immunotherapy and then they progress, you hit them with some chemo or radiotherapy and they have some miraculous responses. Whereas other people, they have upfront radiotherapy or chemotherapy, they have a partial response and then nothing happens. But if you then hit them with low dose immunotherapy you can drive them on to a complete response and I’ve had many patients where I’ve been able to do that. So this is a very, very important concept.

Then I talked about other things which might prime but do not necessarily kill and they don’t necessarily have to be an out and out immunotherapy agent. I’ve noticed that some drugs that we’ve used that are completely non-cytotoxic but cytostatic and when people are on them they seem to prime to respond better to other treatments. I mentioned that there were the cannabinoids, the artesunates and then naltrexone, which is the anti-morphine drug, in low doses seems to have an amazing sensitising effect on the immune response as well as on the targets, the cancer cell lines. That we have shown this, this is a really remarkable phenomenon whereas these drugs which don’t kill but can have a positive effect on the immune response and sensitise the tumour cells for the kill. So it’s not just by themselves but, again, it’s part and parcel in with the other therapies.

Which combinations do you think offer the most promise?

The one I used in particular was the priming with this heat-killed, we call it a vaccine but it’s really an immune modulator. The one we started with was mycobacterium vaccae twenty years ago and after doing about a dozen different vaccines and immunotherapy we suddenly became aware that the people who had done the best were on this simplistic and simplest of all our immunotherapies, and certainly the most non-toxic. So we’ve found very good results in melanoma. To cut a long story short, the people interested in it dropped it and we were able to resurrect it in a new form with a small company called Immodulon who resurrected it. We showed that it was a slightly different agent for manufacturing purposes but it’s just as, if not more, active in melanoma. Then we showed in the laboratory and actually in patients, on a named patient basis, that there was a real synergy with gemcitabine. So at the time we did this it was the gold standard for pancreatic cancer so we said why not do a randomised study gemcitabine with or without this agent. That’s what we did and we’ve got a fantastic survival advantage in those patients with metastatic disease.

We had a little bit of trouble in getting some people to accept what I would as regard the enormity of the result because the gemcitabine patients alone did not last as long as several in the literature but there were very good reasons for this. We started it, the trial, just as FOLFIRINOX came out and then gem Abraxane. So all the people fit enough to go on FOLFIRINOX went on that and gem Abraxane. So we actually had a group of patients which I would say represent the real world; the real world pancreatic cancer patient is not that fit and yet they did so much better when on an immune modulator and, more importantly, gemcitabine plus x always equals side effects – gemcitabine plus x plus x plus x. This is the only study, gemcitabine plus x, in this case this IMM, where the side effects, overall quality of life, was actually better on the combination than on the chemo alone.

Here at this meeting I’m fascinated to see that one of the concepts of this is perhaps you don’t need as high a drug and there we heard from others that when you’re using immunotherapy you can get the same effects from chemotherapy up to 40% of the normal dose. That’s what I’ve evolved into, I never use more than 50% now. So that’s another advantage because even with drugs like docetaxel, carboplatin, they’re not toxic at 50% but with immunotherapy they still work.

What developments do you see on the horizon?

Other things we’re working on at the moment are the drugs that are major modifiers that have no significant toxicity that we can use. What we showed with these drugs is that the way they’re most effective is that when we give them and then withdraw them then the cells that have been exposed to and are no longer exposed to them, they’re much more susceptible to apoptosis and to other forms of cell kill like immunotherapy etc. That’s what we’re working on at the moment and it seems to be the stop-start is much more effective than continuous therapy, and that’s the cannabinoids the artesunates and this drug we’re very interested in, low dose naltrexone, which is really working like an IMiD, immune modulator, of which the last few meetings I’ve been talking about all our work with those so I gave it a rest this time. That’s the Celgene IMiDs, the lenalidomide, the pomalidomide. And two or three other people have pointed out that they greatly enhance the checkpoint inhibitors like PD1 etc. So I gave those a break because Celgene have got those; these are three drugs which have not yet been used but which we hope we will have in the clinic with other treatments in an approved way in the near future.

What’s the take-home message?

We’re getting a lot of lessons out of these combinations and what we’re seeing is in combinations which are really practical, non-toxic and even the ones that have yet to be licensed I think they have, as it would be put today, serious healthcare economic issues i.e. unlike the checkpoint inhibitors, they’re not going to cost a hundred grand a time and bankrupt every healthcare system in the world. If you’re going to combine two checkpoints on a hundred grand each, no healthcare system can afford that, let alone the combined toxicities we’ve been hearing about. So that’s my goal is to be able to do as well as but with combinations which are affordable, non-toxic and readily available. That’s the goal of the Cancer Vaccine Institute that funds me.