Harnessing the immune system to fight cancer, with Nir Hacohen

TRANSCRIPT

NARRATOR
Hi. I’m Lisa Girard, director of scientific communications at the Broad Institute, and you’re listening to BioLogic, the logic behind the science: conversations with Broad researchers exploring what they do and why they do it.

Today, we’re exploring the intersection of cancer, immunotherapy, and autoimmune disease. How can researchers harness the immune system to fight cancer, while leaving the rest of the body unscathed? What makes some tumors more vulnerable than others? And what do we still need to know about the immune system to make this all possible?

Nir Hacohen

Immunologist and geneticist Nir Hacohen is asking these questions right down to the molecular level. Nir is an institute member at Broad, director of the Center for Cancer Immunotherapy at Massachusetts General Hospital, and an associate professor at Harvard Medical School. His research team wants to know what drives the immune system to attack tumors, or to turn and attack vital organs in a person’s body — and how to use that knowledge to inform better therapies.

In one approach to addressing these questions, a study led by Nir and his colleagues, including Aviv Regev (formerly of Broad and now at Genentech), has focused on defining the cell types involved in the immune system — highlighting the value of embarking on a comprehensive Human Cell Atlas initiative, which the international community is now taking on. 

To kick off this episode of BioLogic, Nir explained the importance of understanding specific cell types.

HACOHEN
What we want to understand is how the immune response works in disease — but in order to understand that, of course, we need to define the cell types that carry out the immune response. Now, classically, of course, that’s been done for many many years, but we’re going back to that question, saying, “Did we really define them correctly?”

And so what we do is, by using single cell RNA-seq, we can start to look at the individual cells of the immune system and start to define the subtypes of cells that exist. And rather than just assuming that we know it based on a lot of historical data, let’s just go from the beginning and find, in an unbiased way, the cell types.

And then that would allow us to study the diseases more appropriately, because we can look at the right categories, as opposed to saying, “I’ll name them all T cells.” Well, that’s fine and then you can isolate them with a certain marker, but the T cells are much more complex — and so we need to find the subtypes. And then you can isolate the subtypes and study them. That makes more sense than aggregating them together, because you lose a lot of signal and a lot of understanding when you aggregate.

NARRATOR
Nir and his colleagues used single cell RNA sequencing to identify subtypes of dendritic cells in blood samples. During an immune response, dendritic cells sense the environment and trigger our T cells, which in turn signal our body to mount a specific immune response.

HACOHEN
We focused on identifying the different dendritic cell subtypes in humans and were able to redefine some of them. The ones we think they’re not dendritic cells that people thought they were, we would say, “No they’re not.” We were able to split other dendritic cells into subtypes that we didn’t know existed, and able to discover a new dendritic cell subtype. And we were able to also discover the cell that gives rise to some of these dendritic cells — so, the precursor cell.

And until now, we didn’t have a good way to do this in an unbiased fashion. It was very difficult because we had to make big assumptions about what we were looking at prior to this technology.

NARRATOR
And they’re not stopping there. Nir and his colleagues are expanding this work to look at dendritic cells in different tissues, in order to understand how the cells differ across the body. The researchers are also moving on to other cell types in the immune system to tackle questions about their role in disease.

HACOHEN
And we are already doing that, looking at autoimmune disease and cancer and asking, “What are the cell types in those diseases and what are their functions? How do they contribute to disease? How are they different from the healthy state?”

NARRATOR
The lab is investigating autoimmune disease and immune responses to cancer simultaneously. In essence, these two can be seen as opposite sides of the same coin. In cancer immunotherapy, clinicians are asking the body to attack itself — as it does in autoimmune reactions. 

HACOHEN
For example, is a T cell that kills a cell in your kidney in a very similar state to a T cell that kills the cancer that might be in your kidney? And so, you know, what are the relationships between cells in a cancer situation and an autoimmune situation?

Of course, in cancer, we want them to be in a similar state to the autoimmune disease. We want them to be able to destroy the tissue.

NARRATOR
But there’s an important caveat here.

HACOHEN
However, in cancer, what we want is for them not to destroy the normal tissue — only to destroy the cancer tissue.

NARRATOR
For context, Nir gave us some background on how cancer immunotherapy came about.

HACOHEN
The main breakthrough in immunotherapy came from the discovery — and then application — of what are called “checkpoints.” Originally, we called them, actually, “co-inhibitors” in the immune response. These are proteins that inhibit T cells, and when you block them, the T cells are not inhibited anymore and the T cells become active and that allows them to start to kill tumor cells.

So, the hypothesis is that many people — not all — have T cells sitting there that could be killing the tumor, but are blocked for some reason through these co-inhibitors. So when you block the co-inhibitors with an antibody against them — so for example, anti-PD1 therapies, the most famous now, PD1 protein is a blocker — you give an antibody against PD1, the T cells can be reactivated because their blocking mechanism is gone.

Now, in terms of where we are in the complete response rate — meaning the tumors continue to go down and reduced and almost eliminated or in some cases completely eliminated as far as we can see — the complete response rate for, let’s say, anti-PD1 therapies can be around 9 percent in the best cases in melanoma. So it means one-tenth of people are basically getting a complete response, which is pretty amazing considering that before, melanoma was not particularly treatable. So that’s pretty good, but it still means 90 percent of people are not responding.

NARRATOR
And when clinicians kick the immune system into overdrive to fight tumors, there are side effects.

HACOHEN
About 16 percent of those people will also develop some autoimmune diseases, the ones, you know, from the people who are treated. So there are risks involved as well, because what you’re doing is you’re nonspecifically inducing an immune response.

Of course, yes, that’s good for the cancer — but the body doesn’t quite know what you’re saying.  It’s like, “Oh, turn on all the immune responses,” so you’re not giving it any instructions on what to do.

So the co-inhibitors are the “brakes” on the immune response, but there’s no steering wheel. So you remove the brakes when you give the antibodies, so the car just moves forward but there’s no steering wheel so it goes wherever it goes, randomly.

NARRATOR
In these cases, the immune system will attack the body's healthy tissues.  Immunotherapy is a promising approach to fight cancer, but the field is still challenged by the fact that most patients don’t respond to the therapy — and when they do, many develop autoimmune reactions. 

Now, researchers are looking for ways to increase the specificity of the immune response. One of their goals is to figure out what the targets should be in each patient. Nir explained one approach to this set of problems, focusing on cancer proteins called neoantigens.

HACOHEN
We’re looking for, “What is it that we should be targeting in the tumor so that we get that distinction between your healthy, normal cells and your cancer cells?” And that’s where we’ve been studying these neoantigens, which are the mutated proteins of your cancer, which are presented by your tumor cells to the environment.

So for example, we found that higher mutation-rate tumors have greater immune responses against them, so supporting this idea that the more mutated antigens you have, the more there is for the immune cells to see. Because that’s what makes them different from all the healthy cells around them, otherwise, well, the tumor — nothing would be attacked if it was all the same, so it has to be different.

NARRATOR
Once researchers know the right targets, they also need to figure out how to train the immune system to go only in the direction of those targets — rather than running amok after being stimulated.

HACOHEN
In about 2007, we were starting to sequence tumors here at the Broad, and realized that there was enormous heterogeneity, because next-generation sequencing allows you to get the frequency of each mutation within the tumor. That is what led us to thinking that neoantigens are the trick, because the hypothesis before that was that we could find a universal antigen for tumors and just vaccinate people against universal antigens. The problem is that in tumors between each other, like if you have a tumor and I have a tumor, will be very different.

So what we and others are trying to do is to program the immune response to only see the tumor and not to attack other sites. And that’s the challenge for the coming years. It’s not an easy challenge, obviously it hasn’t been solved before, but we believe we have enough data to support the neoantigens being the right target. And the analogy we use is that’s kind of the “steering wheel.”

So what we do with the neoantigen approach is we sequence deeply into your tumor and then we create a polyclonal vaccine, meaning we target 20 neoantigens that cover the diversity of clones that exist in your tumor. So, it’s in fact a personal vaccine, in the sense that only the person who we give the vaccine to can receive that vaccine.

What the neoantigens do, as a vaccine, is give you a steering wheel and say, “Go towards the tumor, not towards other things.” And so you focus the immune response more generally. And you can still remove the brakes, but you don’t have to remove them as much because you’ve already boosted a response against the right thing.

NARRATOR
But most tumors aren’t sitting idly by, waiting to get destroyed by the immune system. Nir explained another hurdle his team has encountered.

HACOHEN
Tumors have come up with tricks. And the most common trick we found, and that’s probably the most common in the world of cancer, is that the tumors actually lose the ability to present the neoantigens and the other antigens on their surface. They lose what’s called the “presentation machinery,” so they make mutations in those genes involved in presenting antigens on the surface.

So if they can’t present the antigens, no one can see them. They’re essentially invisible. And so one of our tactics in our work on the therapeutic side is to actually induce an immune response quite rapidly so that the tumor doesn’t grow too much and continue to evolve and mutate and create essentially a resistance. So now the challenge for us is to keep getting it to work and moving it forward.

NARRATOR
In all of his research, Nir draws his approach from physics, the field he first started in.

HACOHEN
Physics, to me, was the most elegant science to study as an undergraduate because of the simplicity of the theories. But I found myself always drawn to the open problems in biology.

In physics, when you come up with a theory, it’s gotta explain multiple phenomena. It’s gotta be more complete. And so that kind of thinking that comes from physics really makes me want to be very thorough and complete and systematic, and come up with an underlying theory for things — which is not easy in biology, because there often isn’t. It’s much more complex. But I do try to bring that along whenever I can, and I think it helps.

NARRATOR
You can check out other areas of Nir’s work, and learn more about the Immune Cell Atlas and the Human Cell Atlas project, featured on broadinstitute.org. Other episodes of BioLogic are also available at broadinstitute.org, and through SoundCloud, iTunes, Pocket Casts, and other podcast distributors.

For the Broad, I’m Lisa Girard. Thanks for listening!