“If It Can't Kill, It’s Not Effective.” How Understanding T-cell Exhaustion Can Improve CAR T-cell Therapy

Benjamin Youngblood, PhD, talks with Pharmacy Times about the fundamental process of T-cell exhaustion, the importance of the T-cell signaling molecule, CD8, and how his team is leveraging it to improve cancer therapeutics.

Q: What is T cell “exhaustion” and how does it impact CD8 T cell responses?

Benjamin Youngblood, PhD: Okay, so epigenetics controls the state that the CD8 T cell is in. So it controls a cell fate decision the CD8 T cell goes through. And so what we've learned is that there has to be a very specific range of development that the T cell has to be in, in order to mount a therapeutic response. And so epigenetics controls that decision to go from the functional to the dysfunctional state. Understanding epigenetic mechanisms can keep you in a more functional responsive state.

So exhaustion is a process whereby the CD8 T cell sees its antigen– and if you control the source of antigen quickly, you don't undergo this process of exhaustion. But if the source of the antigen is sustained, then you have to blunt that effective response– because it's actually toxic to the individual. So CD8 T cells mount a very potent effective response. If you can't control the source of antigen, then you'll keep mounting that really potent effective response. So exhaustion is sort of a sort of a failsafe on turning it off if you can't control it.

If you have persistent exposure to an antigen, you eventually shut that effector response down. Why it's pertinent to cancer is that it’s probably an evolved mechanism for viral infections. If you have cancer, though, the same mechanism is in play, where you have this progressive suppression of the effector response. And we need to keep the cells in a more functional state to make them therapeutically effective. So CD8 T cells are an affected response… it's overdrive. And so you can't sustain that or you'll kill the host.

Exhaustion is an intrinsic mechanism to the T cell to turn off that overdrive mechanism. It’s suppression of the effector response. That occurs progressively with duration of exposure to antigen. What we've been doing is defining the different stages of exhaustion in that terminal state. And you can figure out when there's a point of no return, where the T cell gets committed to that terminal state and will no longer mount an effective response.

Q: What is one of the most exciting findings made by your team in relation to T-cell exhaustion?

Benjamin Youngblood, PhD: I think defining the precursor subsets of the progenitor subsets to exhaustion is going to allow us to better define individuals that could be responsive to checkpoint blockade. You can also potentially figure out ways to expand the subsets of cells, so you can mount a more potent or numerically greater effective response. It's that progression from that effector. So basically, the cells change.

Some cells have just committed that have seen antigen a long time– some are less committed. It also depends on where they sit in the body. If you can identify the cells that give at the beginning of that differentiation process, those are the ones that give rise to all these different effector populations, and you can elaborate on those. That's some recent work that's come out of several labs.

And then I think there's a lot of implications for CAR T cells or adoptive T-cell therapy to identify that multipotent progenitor population and figuring out the mechanisms that allow it to remain developmentally plastic.

Q: How has the role of epigenetics evolved over the past century?

Benjamin Youngblood, PhD: Epigenetics, as I said, controls the cell fate decision. So to become an effector cell, you open up, or you epigenetically remodel the chromatin effector low side becoming accessible. And those are epigenetic marks to the DNA.

The same thing happens when you start to shut down the T cell effector response ability to proliferate or express these effector molecules that allow for recruitment of other cells or direct killing. By understanding those epigenetic processes (when they are acquired), you can decide when to block them and what cells you want to pull out of the person to block them in.

I think it parallels the increases that we've seen in depression, anxiety, and substance use. It's like it was a great kind of shake up and trigger for our underlying mental health vulnerabilities. And also, with the isolation that came along with it, it seemed to have there seems to have been a magnifying glass that was  put on these conditions- and the urgent need for treatment that comes along with it.

You start from a very naive state– naive T cells have never seen this antigen (in your lymph node). And what happens during a primary immune response is you have naive T cells going in and out, circulating in and out of your lymph nodes. They are surveying to see if there are antigens there. This happens a lot.

Then you have an antigen-presenting cell that brings the antigen into your draining lymph node. A T cell encounters that, says, “ah, that's what I'm specific for,” then it mounts clonal expansion– the cells can expand now that they've seen their cognate antigen. This surveying happens a lot, the antigen in the T cells being brought into this very specific region.

Once it sees its antigen, then they expand upwards of 100,000-fold. Once they reach a threshold, they exit the lymph node, circulate to the source of antigen, and hopefully control it. So, depending on where that source of antigen is (and how big it is…how big that source of antigen is), the T cells may or may not be able to control it and clear it.

This whole process involves epigenetic changes to the genome that allow it to traffic to the site, and source, of the antigen to mount an effective response. So the T cells get there. And they say, “Yeah, we control the source of antigen.” They know that because there's no more sensing the antigen ([done] by the T cell). Or they just can't and those T cells become suppressed. They change their genome so they don't keep expelling these cytotoxic molecules.

Q: What is the value of this research in the field?

Benjamin Youngblood, PhD: Okay, so CD8 T cells are the killing force behind checkpoint blockade. When you hear programmed cell death protein 1 (PD-1) blockade, they're the ones that are killing the tumor. With CAR T cells, there’s a lot of discussion now. But CD8’s do a lot of the killing for the CAR T cells. You engineer them with a new receptor, but they go and kill the tumor. But if you take a cell that's not functional anymore, it doesn't matter what you engineer it with (or if you do checkpoint blockade)- If it can't kill, it is not effective. Finding that point before it turns off the killing capacity is critical. That’s what we've done. We've identified the epigenetic checkpoint that blocks the cell from being functional. And by doing that, we're able to engineer CAR T cells so that they remain functional.

For as long as we've ever looked, they can sustain that anti-tumor response. We've figured out the molecule that blocks (enforces) suppression. We've deleted it in our CAR T cells. And now what we show is you can sustain that anti-tumor response in settings where normally you wouldn't be able to control a tumor. Now you can because you sustained an effector response.

Q: Closing Thoughts?

Benjamin Youngblood, PhD: This was founded in mouse research, and I think it's really exciting and an example of how exploring a basic mechanism of T cell differentiation can pretty quickly be translated into a therapeutic approach that has major implications for the broader public. And so I think it's one basic study–  basic science research should be supported more because this is a great example of how it can be translated.

We're very interested now in kind of going back and looking at the general mechanisms that we've identified, taking a broader look at the mechanisms we have identified, and the other regulators in that process to figure out how to get a better handle on this process of T cell exhaustion. And how these multipotency regulators really do impact the CD8 T cell differentiation.