ASH 2015

Immunotherapy makes patients’ tumours "melt away"

Dr Joshua Brody - Mount Sinai Medical Center, New York, USA

Immunotherapy is quite a buzz word in cancer at the moment and a long time ago it was, people had great hopes from it, but now there’s all sorts of excitement. You’re doing something called in situ vaccination, what is that in principle?

Immunotherapy is a very buzzy word and we are delighted that it has gone from a great idea for decades, literally, as you say, to a great therapy. We’re actually making patients’ tumours melt away, even large bulky tumours. We are focussing in this presentation here on something called in situ vaccination. At its simplest this is where we administer, inject, immune modulators directly into patients’ tumours to turn on the immune system locally and then get systemically the immune system to eradicate tumours elsewhere.

What are these novel immune stimulators that you’re having great hopes of right now?

Most commonly we’re talking about a group of immune modulators called toll-like receptor agonists. Toll-like receptors won the 2011 Nobel prize, they are amongst the best switches on many important immune cells and most famously on dendritic cells for the other part of the 2011 Nobel prize. So we inject toll-like receptor agonists directly into these patients’ tumours.

And, importantly, they can be specific?

They are quite specific, these toll-like receptor agonists, for the toll-like receptor molecules that they target. They are quite specific for the cells that express those molecules and, by virtue of intra-tumoural administration they have their effect locally at that tumour site, educate the immune cells there to taste the immune system systemically to get rid of tumour cells.

You’ve been doing some preclinical work that’s being presented right here at Orlando at the American Society of Haematology, tell me what you’ve done and what you’ve found.

These toll-like receptor agonists are an exciting class of medicines. We’re a bit limited, we have a handful of clinically available reagents, we have things called TLR9 agonists, TLR3 agonists, that we use in our patients, even TLR7, 8 agonists, but we’re limited. What we’re presenting now is an approach to try to go beyond those limitations. Toll-like receptor agonists are synthetic molecules that look like virus-like or bacterial-like particles. We are taking a step back and saying we have access to actually safe and easily accessible viruses and bacteria in the many vaccines that we all receive, measles, mumps, rubella vaccine, typhoid vaccine, anything that we already use for our patients. Those things in them contain toll-like receptor agonists and we have now used those to try to induce the immune system in these tumours.

In what systems?

In this case all entirely in pre-clinical lymphoma models which is where we have done most of our work. Again, in our patients we have trials for other tumour types – breast cancer, melanoma, sarcoma, head and neck cancers.

And how are they looking in these models?

In the models these intra-tumourally administered toll-like receptor agonists look amazing. We have large pre-clinical tumour models of the tumours melting away and that’s been very exciting for us. We have also some early clinical data as well.

So in the early clinical data what are you doing and how might these stimulators be used in the real world in the future?

We’ve actually completed some of the first clinical trials. When I had been working at Stanford for nine years previously we did trials for a total of 60 patients with different types of low grade lymphomas, injecting a TLR9 agonist into patients’ tumours which saw those tumours melt away, but more importantly we saw far away tumours melting away as well. Some of those patients had remissions that lasted a long time, measured in years. What we have done a little differently now at Mount Sinai School of Medicine is to bring one other ingredient to this which is to bring more of those immune cells to the tumour type. Again, we’ve seen in the first few patients systemic remissions of low grade lymphoma.

What’s different about this approach, using these toll-like receptors, as compared, for instance, with checkpoint inhibition which also gets the T-cells working again?

Absolutely. There’s a fundamental difference and also that difference is probably why these approaches would probably synergise very well with checkpoint inhibitor therapies. The big difference is that checkpoint inhibitor therapy usually relies on a pre-existing anti-tumour T-cell response, an anti-tumour immune response, and it cuts the brakes of that immune response to free up those T-cells to more effectively get rid of tumours. But it relies on usually T-cells already being at the site of the tumour. Our approach here is complementary, we are able to bring T-cells to the tumour site and activate them first.

But it sounds a bit hard to do because you’ve got to have a superficial tumour, so metastases maybe, and you’ve got to inject them all. Is that really possible to do a clean job of it all?

It’s a good question. I would say that it’s incredibly simple to do for this class of tumours which are superficially manifested – lymphomas, melanomas, other skin cancers, some breast cancers, head and neck cancer, sarcoma. For those it’s simple and straightforward to do. We take a needle, inject it right into the tumour, the patient is in and out in five minutes. It’s not nearly as complicated as other manoeuvers we do like a bone marrow biopsy, it’s about as complicated as a blood draw. But the opportunity to do large trials will require everyone to be comfortable. There is now an FDA approved medicine using this intra-tumoural approach with an oncolytic virus, so I think that will get the comfort with greater mass appeal.

Doctors are already getting excited about these immune approaches, all of the immune approaches, what should they think about this one?

The excitement about immunotherapy is largely there because of checkpoint blockade and maybe some other approaches like chimeric antigen receptor therapies. The question is how to make checkpoint blockade better. Checkpoint blockade is great for a minority of patients with melanoma, with kidney cancer, bladder cancer, lung cancer. This still leaves a vast majority of patients we need help with. The most commonly asked question is how do we combine the next ingredient with checkpoint blockade. I think what we need to do is combine safe therapies with checkpoint blockade. If we call checkpoints the brake pedals of the immune system and some of these costimulatory molecules gas pedals of the immune system, we also need to bring in a steering wheel for the immune system which is vaccines. Once we cut the brake pedals we want to guide the immune system towards what it should be hating and eliminating and that’s what vaccines are there to do, in situ vaccines included.

So in brief, do you think we’re looking at a future with possibly combination immunotherapy head of the list?

I do and it’s the near future, it’s not the distant future. Some of these trials are already starting, most famously with, for example, the oncolytic viruses that are now approved for standard therapy of melanoma to be combined with checkpoint blockade therapy. We have other trials of toll-like receptor agonists combined with checkpoint blockade therapy and I think those combination therapies will be very exciting.