Immune systems tackling cancer

16 April 2019

Interview with 

Joshua Brodie, Mount Sinai School of Medicine

VACCINATION-INJECTION

Vaccine injection

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One in three of us will develop cancer at some point in our lives. And, thankfully, in recent years treatments have improved dramatically; in fact we can now hold many tumour types in check, for considerable periods of time. But the therapies that do this are extremely costly, and they can have significant side effects. Which is why researchers are particularly keen to make better use of a free, natural resource available to all of us: our own immune systems. The immune system doesn't usually target cancers because it recognises the cells as part of the body. But a new study in Nature Medicine has found that with the right signals injected - like a vaccine - into a tumour, it’s possible to persuade immune cells otherwise. Chris Smith spoke to Joshua Brodie from the Mount Sinai School of Medicine in New York...

Joshua - We refer to it as in-situ vaccination. All it really means is we are making the vaccine at the site of the tumour by injecting immune stimulants directly into the tumour to try to trick the body into thinking that this cancer is like an infection, so they can learn the lesson at that tumour site and then travel throughout the body to eliminate tumour cells wherever these immune system cells can find them.

Chris - And what do you put in? When you say you’re put in immune stimulants, what are they and what are they actually stimulating?

Joshua - Sure. It’s a great question and it requires one key bit of background which is the 2011 Nobel Prize was awarded for this crucial immune cell called the dendritic cell. If we think of most of the immune cells, we call them T cells, as soldiers of the immune army, the dendritic cell is the general of that immune army and it instructs the soldiers who to attack and eliminate.

The first immune stimulant that we inject into the tumour is something called Flt-3L, and we administer Flt-3L directly into a tumour. We bring many dendritic cells to that tumour so they can start to see what the tumour features - we call them antigens - are that we want to recognise.

Chris - So that's a bit like your taking a war analogy, sounding the bugle at the site of the tumour so that these dendritic cells which have the ability to marshal immune effectors, these T cells, they’ll come in but they've got to have something to work with, haven't they, so how do you get the dendritic cells to then pay attention to the tumour cells?

Joshua  - Sure. So the second ingredient is something called low-dose radiotherapy. It's basically just a very small dose of radiation to that tumour which kills a few tumour cells, releases their antigens, and those dendritic cells then gobble up the antigens so they will be able to present them to the immune soldiers, to the T cells. It will go even beyond a bugle, it will be a bugle plus a PA system.

And then ingredient three is another immune stimulant that we inject directly into the tumour and it's called a Tlr, a Toll-like receptor, agonist, and it activates those dendritic cells to convey that these tumour antigens are like an infection, these are something that we should attack and those dendritic cells then instruct the rest of the immune soldiers on what to recognise and what to eliminate throughout the body.

Chris - What's the evidence this works though?

Joshua - We in this paper describe the in-situ vaccine in two very different contexts. We describe in the lab, using animal models, where we really prove exactly how it is working, and then we brought it into an early phase clinical trial for patients with advanced stage non-Hodgkin's lymphomas. And we've had some patients with partial and complete remissions of their cancer, and those remissions have been going on for months or years for some of these patients.

Chris - Now so far, you've talked to me about attacking non-Hodgkin's lymphoma; these are cancers of some of the white blood cells. Could this same strategy though be used for other types of cancer; for instance melanoma - very common cancer of the skin, could you treat that with this?

Joshua - We believe it would work for most types of cancer, if not every type. In the lab we actually have studied melanoma where we showed pretty similar and very good results and really our next direction is to bring this into a clinical trial for patients. In fact, that follow-up trial is already just opened this past month and that trial will treat patients with lymphoma or breast cancer or head and neck cancer.

Chris - Sounds terrific... but. And there's always a 'but' with these things isn't there? One has to be cautious because is there not a risk, given that there will be some healthy normal cells and antigens in these tumours, that the immune system could begin to respond to perfectly normal signals on normal cells, as well as the bad markers signalling cancer cells and you might end up with an autoimmune disease where the immune system turns on itself?

Joshua - Chris, absolutely. In fact, that's the primary concern with all these types of immune therapies. As we push the immune system, we might possibly push it too hard and it could attack both cancer and some healthy cells as well. What you say is exactly correct; in a very small percentage of patients that could happen with some of these immuno-therapies. With the vaccine approach, we think there is at least some more specificity. But you're right, there could possibly still be healthy cell antigens within that tumour. We can only say so far that we've done this in a number of patients and we have not seen that so far. But you're right, we definitely have to be wary of side-effects as we push ahead, certainly.

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