How Immunotherapy Could Help Us Beat Cancer: Deepta Bhattacharya (Transcript)

Here is the full transcript of Dr. Deepta Bhattacharya’s talk titled “How Immunotherapy Could Help Us Beat Cancer” at TEDxUArizona 2024 conference.

Listen to the audio version here:

TRANSCRIPT:

I’m an immunologist, and for the past 15 years or so, my research group has been studying how the immune system responds to infections and vaccines. I’d say up until about four years or so ago, even when I tried to explain the research to my own family, the response was a bit like, “Oh, that’s nice, dear.” Right.

But with the onset of the Covid-19 pandemic, everything changed. And all of a sudden the details of what we study, you know, immune responses to the virus, what the virus was doing, whether or not the vaccines would be successful, all of these kinds of things become of great interest to the global public.

And while I was perfectly comfortable talking about some of these issues with my colleagues who are trained immunologists, I and many others were then suddenly tasked with communicating these complicated concepts to the general public, who are now all of a sudden very interested. And I think it’s fair to say that none of us really had any practice or, frankly, skill in this arena.

And so the advice that I was often given was to simplify, craft my message so that it could be understood by sixth graders. And that’s exactly what I did at the beginning. I tried to simplify things so they could be understood by elementary schoolers. And I thought I was really killing it in this process. Right.

And so then when I went around looking for the throngs of cheering sixth graders who were hanging on my every word, what I instead found were groups of people who were deeply interested in the details.

The bottom line is, if you’re actually trying to look up to see what I have to say, then the reality is that you’re probably interested in the deeper science.

And by simplifying just for the sake of simplifying, I was sort of doing a disservice because I was glossing over some of the complexity that I think, anyway, makes the immune system just beautiful to study. And by glossing over that complexity, I think what I was also doing is losing an opportunity to communicate not only what’s happening in the context of the Covid-19 pandemic, but the future of immunological therapies.

So today, I’d like to correct for my past transgressions and not dumb it down for you at all. Instead, what I’m going to do is to try and make complex topics understandable and explain how the immune system works.

The Adaptive Immune System

So I’d like to first start off by talking about a term called the Adaptive Immune System. I’m sure you’ve all heard of the immune system. Maybe some of you have heard of the adaptive immune system. So what is that?

To understand that, I think we need to go back through some historical context. We’ve known for millennia that the immune system is actually really good at dealing with all sorts of things that come its way. You get infected with a virus, you clear it, you get infected with a different virus, you clear that a bacteria fungus, a parasite. The question has always been, how does the immune system deal with such an array of diverse threats?

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Back before we really knew, one of the theories had been that the immune system, the cells that it produces, are a little bit like Silly Putty. They’re just sort of lying in wait. And so when it encounters a new virus, it sort of molds or adapts itself to that particular virus. So that’s the origin of the term, the adaptive immune system.

But what we’ve learned from decades of basic research is that that’s not exactly how it works. And instead, what happens is that the immune system starts developing enormous numbers of cells, each one just a little bit different than the other. You can think about it like a series of keys, and instead what it does is it basically generates an enormous numbers of keys, each one of the slightly different shape than the other. And those keys are basically floating around your body looking for any signs of things that are different than yourself.

If it happens to encounter something like a virus, and maybe only 1 in 100,000 of those keys would actually fit, then those keys then start to lock in to that virus and turn it so that the virus can’t replicate anymore. Not only that, it’s generating enormous numbers of copies of itself so that if that virus or that bacteria or that fungus ever tries it again, your immune system is going to be ready. So that is the central tenet of how the immune system and the adaptive immune system works. It can distinguish things that are yourself from things that are not yourself, and it remembers when it actually recognizes something.

How mRNA Vaccines Work

So that’s the basis for how these mRNA vaccines that we’ve heard so much about work. And I’d like to take just a little bit of time talking about exactly that. So how do these mRNA vaccines work and how does it interface with the adaptive immune system to give you immunity?

What these vaccines do is that they instruct your cells to start making a protein, the spike protein that is not normally made by your own cells. So thus that becomes a target for the adaptive immune system. There’s a couple of different ways in which the adaptive immune system then engages this spike protein that’s being made by your cells to then it lock it down and then be ready in case the virus actually comes its way.

One of the components of the adaptive immune system, a subset of these keys that I was talking about are called B cells. These B cells can then recognize the spike protein that’s being made by your own cells. And then start making many more copies of this of themselves, and at the same time start making a whole bunch of antibodies, which are proteins that fit into the virus and the spike protein to keep it from replicating or infecting itself. So these proteins are basically there to deal with the virus when it’s outside the cell, and it’s trying to get inside.

Another type of immune cell are called T cells. These are a little bit different, because now these are actually looking for cells that have already been infected. And the way that they do so is that the cells that have been infected start chopping up the viral proteins in a little bits, and then presenting those little bits on the surface to see if any T cells recognize it. And if a T cell does so and sees that there is a virus that’s inside the cell, then they also start making many more copies of themselves, engaging mechanisms to try and shut down the virus, including by killing the cells and interrupting the viral life cycle.

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So this is the key basis of how these mRNA vaccines work. They basically train your immune system to be ready in case that virus actually comes your way a little bit later, preventing infections outright or at the minimum, preventing the severity of the disease. And this is the central basis of not only the mRNA vaccines, but how the adaptive immune system works and the success of all these different vaccines.

Applying Immunology to Cancer

Now, if you think about the central tenet of how this adaptive immune system works, self versus non-self, and you let your imagination wander a little bit, you can think about other ways in which we might be able to aim the adaptive immune system towards other types of diseases besides just infections. So for example cancer.

So what is cancer? How does it work? What is it actually? What leads to cancer? What leads to cancer are mutations. Your cells throughout your lifetime are picking up mutations throughout its genome all the time. And the overwhelming majority of these mutations are of no consequence. They don’t really matter, but simply by bad luck, some of those mutations will land in genes that are normally there to keep your cells from dividing when they shouldn’t.

And if you pick up enough of those types of mutations, then your cells that are otherwise normal start to turn into cancerous cells. Those cancerous cells will start to divide and generate tumors. And that’s the basis of cancer. Now, one of the things that happens when those cells are picking up those mutations is not only is it changing the functions of those genes, it’s also turning self proteins into non-self proteins, which then also then becomes a target potentially for the adaptive immune system.

Now we know that if the cancer is ongoing and it’s growing, the adaptive immune system is failing at its job. It’s not clearing out the cancer despite the fact that it maybe it should be able to. So in this case, probably what it needs are some instructions. Just like the Covid-19 vaccines provide some instructions to the adaptive immune system to be ready for the virus, perhaps there are ways to provide some instructions to the adaptive immune system to deal with cancer.

One of the things that our group did in the context of the Covid-19 pandemic is we looked to see how well those Covid-19 vaccines were working on cancer patients who are on active chemotherapy. And it turned out that it’s actually working pretty well, surprisingly well, because a lot of times these chemotherapy regimens can suppress your immune system, and at least for other types of vaccines, can really suppress how well they work.

But for the mRNA vaccines in our hands, what we saw, they are actually working pretty well, especially if you got an extra dose. So it opens up the possibility again that in these cancer patients, you might be able to use these mRNA vaccines to instruct the adaptive immune system to attack the cancer in this case instead of the virus. And so that’s the general idea here, right?

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Customized Cancer Vaccines

So what if you might be able to take a person’s cancer cells, sequence those, those tumors to figure out what mutations are in there, which ones are causing the cancer, and then in a customized way, build out these mRNA vaccines to vaccinate patients against their own cancers? It sounds kind of fanciful, like a bit like science fiction. But it’s not. Just earlier this year, researchers at Sloan Kettering did just this, and they basically did follow this workflow for people who had pancreatic cancer, which is a particularly bad one.

The five year overall survival rate is quite low for this type of cancer. And what these researchers found is that half of the people that enrolled in their trial were able to generate massive T cell responses aimed at the mutations in the cancer and not at the normal cells. It’s just a remarkable result. And for those people, their cancers did not recur over the course of about two and a half years.

Again, for this type of cancer, that’s just a remarkable result. So I hope you can understand why we’re so excited about the future of immunotherapy. And by understanding the basics of how the process works, you can think of new ways in which you might be able to aim the immune system beyond just infectious diseases, to other things like cancer. Now, I will say that in this trial, half of the people responded, but the other half didn’t.

So well, we know from early returns that this type of approach is working well for some cancers and not for others, and we don’t know why. So I think the only solution to this now is to go back to the basic research to help us understand why it works sometimes and why it doesn’t work some other times, and then reiterate to push those basic findings back into translational therapies. And so for that reason, the University of Arizona and many other institutions now are setting up new centers to study immunology and immunotherapies to try and accelerate this cycle of basic research and translational innovations.

Conclusion

Now, what I hope I’ve left you with at this point is that the complexity is where the beauty lies. And what I really wanted to do today is to bring you all as part of the conversation, so you can understand where the future of immunotherapy is going and be excited, just as excited about it as I am. Thank you.