Christian Ottensmeier: Fighting cancer with vaccines
Image courtesy of Christian Ottensmeier
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John talked about how vaccines can train our immune systems to fight off infections, but what about training programmes for other diseases? In recent years we’ve seen the rise of immunotherapy for treating cancer - these are drugs known as checkpoint inhibitors that activate immune cells to recognise and destroy tumours. They’ve been transformative for some patients, and netted a Nobel Prize for their discoverers James Allison and Tasuku Honjo, but they don’t work for everyone. So, there’s clearly more that we can do to kick the immune system into action against cancer.
One of the researchers who’s dedicated his career to trying to do just this is Christian Ottensmeier, a consultant medical oncologist and Professor of Immuno-oncology at the University of Liverpool. He’s particularly interested in the promise of vaccines not to prevent cancer, but to treat it once it’s growing in the body, by training immune cells known as T cells to recognise its presence and go on the attack.
Christian: The first piece is the knowledge that immune cells can recognize cancer cells. And that initially came from the observation when you looked at cancer samples under the microscope, you found that many of them contain immune cells and particularly T cells.
Christian: T cells are called T cells because they grow up in the thymus. The thymus is a gland behind the breastbone. All our T-cells are born in the bone marrow. Then they go to school in the thymus. They're trained against a curriculum which essentially tells them what to not recognize. You know, in school we get to train what to learn, and the thymus is a school where you train what not to recognize.
Christian: And the guys that do nothing at all, they're sort of culled by neglect. The guys that are really good at recognizing healthy structures, they're removed because they're dangerous. And then you're left with a large range of cells, T cells that leave the thymus, they graduate from school, and they begin patrolling our body.
Christian: Now in the cancer tissue, the key information we need to take into consideration is that actually 99 or so percent of what is in the cancer cell is actually very similar to healthy cells. So you have then the problem that the cancer cells gradually become, over time and often over years, sometimes over decades, more abnormal.
Christian: In other words, they gain features that make them behave differently to healthy cells. And if that is a process that is driven by genetic change, then the genetic change can enable molecules to be made and read from these genes that T cells might be able to recognize. We can say as an overall summary, the cancer cells are visible to T cells, if the T-cells find something that is interesting. If they find something that is interesting, they can attack the T-cells. If that is successful, you get rid of the cancer.
Christian: Cancer vaccines at the heart of the matter try and train T cells to recognize differences. What we've learned over the last sort of 25, 30 years is that you can read out the molecules that make cancer cells different to healthy cells and that you can then take those differences and turn them into synthetic molecules - and you can turn these into a vaccine, give them to the patient.
Kat: What are the advantages of using nucleic acid vaccines for this training of the T-cells? How does that work?
Christian: The advantage of nucleic acids is that they are really easy to adapt to the purpose that you want them to be used for.
Christian: Nonetheless, these nucleic acid vaccines only work if the cell that you are vaccinating actually needs to take the genetic code, make RNA from it, turn the RNA into protein. So the DNA and also RNA vaccines are quite a step away from the final chemical product - the peptides that wake our T cells up.
Christian: But because we know so much about how these processes work, it's been possible to make DNA and mRNA vaccines that really reproducibly make these steps happen, and in such a way that you can reproducibly train immune cells in the patient.
Christian: The other advantages are that these mRNA and DNA vaccines are quite straightforward to manufacture. You can make lots of it really quite quickly and beyond that additionally, DNA vaccines have the advantage that the DNA is really stable. But of course, that advantage is only useful if the final product using the material as a vaccine actually turns into something useful clinically, and their DNA vaccines are behind the mRNA vaccines because with COVID, the mRNA vaccines have been used so widely that they've become household names.
Christian: I think what will be needed going forward then is to figure out which of these types of approaches actually is better and we just don't know that yet.
Kat: So where are we with these vaccines in terms of clinical trials? Where's the edge of the field at the moment?
Christian: The first vaccine licensed in the Western world for cancer was actually a personalised vaccine in which immune cells from the blood were harvested from men with prostate cancer, and then were fed with one of these molecules that is special to prostate cancer cells in this case.
Christian: This molecule was loaded into the immune cells that had been harvested - these cells are called dendritic cells. And then the final product, these mature dendritic cells, were given back to the patients as a vaccine. So that was the first objective evidence that cancer vaccines can attack and benefit patients with advanced cancer because it was very difficult, very expensive, very labor intensive, very complicated.
Christian: The field has galvanised in December last year. And that was the result of a clinical trial in which an mRNA vaccine that encoded unique differences from the cancer cells of patients with melanoma was used in patients who had all their cancer removed, and who were at high risk of developing recurrent melanoma.
Christian: Half of the patients got standard immunotherapy, and we know that that in its own right cures a significant fraction of patients. So if you have patients with very high risk melanoma, you remove this disease with surgery, then roughly half of the patients will eventually relapse. Half of those potential relapses are treated successfully and prevented from relapsing with an anti-PD1 antibody - and the addition of the vaccine halves the risk yet again.
Christian: That was the first randomised data set in the literature that showed that nucleic acid vaccines can actually do the trick and do something really useful. I think we will see new studies emerging, and what then ultimately is needed is to figure out how good is this stuff actually, rather than how good are the ideas that you dream up when you think of the ideas first?
Christian: To that end we'll need comparative data. If we were to compare patients who have, versus those who have not been vaccinated, we can reproduce this kind of benefit in patients with a cancer that has so far escaped any benefit from immunotherapy. And so the time for comparative studies will come in the next five or 10 years I think.
Christian: If you tick those two the boxes, then I think everybody will scramble to become a vaccinologist. And that is very much the sense of what I'm seeing in the community now.
Kat: Casting your mind forward maybe five or so years, where would you hope to be with therapeutic cancer vaccines?
Christian: I hope, but I think, know and fully expect that in five years some of these drugs will be on the shelf as medicines.
Christian: I think that we will look at the patient's cancer. We will make a decision or identify which category, immunological category, the cancer falls in, and then we'll begin making decisions about what drugs to use to manipulate those categories.
Christian: Tumours where there are lots of immune cells, they're all just sleeping - you ring the bell with an anti-PD1 antibody and wake the T cells up. Tumours that have no T cells - you need to use a vaccine to make the tumour visible to the immune system, train new T-cells against what hasn't happened spontaneously. And then there'll be other categories. So I predict that cancer vaccines in the next five years will become indispensable building blocks for combination immunotherapy.
Kat: It's interesting, the new era of immunotherapy for cancer, because we are moving from a position where some of the people who are being treated, they were not likely to survive in the long term or in some cases, even in the medium or short term. But we're getting to a point where what scientists call durable remissions or what, I guess most of us would think of as actual cures, like the cancer seems to have gone and it does not seem to be coming back.
Kat: Is that an era that we are going to start increasingly moving towards, as we understand more about the immune system, its interplay with cancer? Is that something that we can hope for?
Christian: Yes, absolutely. And I think we're there.
Christian: When I started in my oncology practice and started treating patients with melanoma. We did trial after trial after trial, and we never really made anyone better with the outside chance of the odd individual who might get off the hook. Less than 1% of patients. Now we fully expect that in many solid cancers we would cure about 25%, so about a quarter of our patients.
Christian: That's really changed the way we think about it. It's no longer enough to not be able to help the majority of our patients - and for our patients, they now have the expectation that well find me a treatment that will make this problem go away.
Christian: So there has been from almost a sense of nihilism about what we might be able to achieve to now a period that started in 2011 with this first big paper, identifying a drug called ipilimumab as being able to lead to long-term remissions in patients with melanoma - 17% that was. Now we are routinely hitting 25%, in melanoma we are now routinely hitting 50% of patients who have long-term benefit.
Christian: I think what is happening, if you imagine it like a cake, we've taken one slice out of the cake with checkpoint inhibitors that accounts for maybe 20 to 25% of the cake. And now we're trying to whittle away at the rest of the cake. I'm convinced that we will be able to do much better than we are currently doing in the next three to five years, and I believe that cancer vaccines will play an important role in that.
Christian: Whether we'll ever get to a point where we can just eat the cake, in other words where we can cure everyone with cancer - that I don't know, and I think that's quite unlikely, but I suspect that the percentage of people that we genuinely cannot help will get smaller and smaller.
