Should T-cell be profiled for fitness (not exhausted) prior to using T cell-redirecting?

The effectiveness of T-cell redirecting therapies may hinge on a simple factor; how fit a patient's T cells are. Researchers are working to better understand, measure, and even rejuvenate these cells. Which leads to an important question. Should T cells be profiled for fitness before using T cell redirecting therapies?

T-cell redirecting therapies or bispecific antibodies. Treatments where we use the body's own immune system. Recruit the body's own T-cells. They're called killer T-cells. So their normal job is to get rid of cells that shouldn't be there. Either cells that are infected with viruses. If you have a cold, if you have a virus infection or, malignant cells such as myeloma cells.

Myeloma cells, though, have a tendency to hide from the immune system and then grow. So what we do with these bispecific antibodies is that we have an antibody that looks like a Y, where one arm holds on to the myeloma cells. And there several different targets that we have there. BCMA, GPRC5D, those are the approved ones. There is trials ongoing also with FcRH5.

So different types of targets that you can hold on to or bind to on the myeloma cell. The other arm binds to CD3 on the T cells to recruit the T cells, bring them close to the myeloma cell, and then show them that this is the cell. Activate them and and show them that this is the cell that should not be here, that you should get rid of

The key is though to have T cells that you can recruit and that are active and that are not exhausted. So you if you recruit them, you want to be able to activate them so they can then do their job and kill the myeloma cells.

Why do these treatments not work for everyone?

So one of the reasons is that if the target is gone, if the arm that should be holding on to the myeloma cells, the target is not there, they can't bind to the myeloma cell and then the treatment doesn't work.

The second reason why they may not work for everyone is that if we recruit the T cells and the T cells are not active, they're exhausted, and they've been trying to fight the myeloma. The myeloma has been there for for several years. So they can have this exhausted profile.

So if we look at them, we can look at them in different, several different ways.

One of them is to look at the profile on the cell surface. They can be, exhibiting markers that what we call the exhaustion profile.

So even if we try to recruit them, we try to activate them. They're not able to they're kind of too tired and exhausted to do their job and to kill the myeloma cells. So, yes, this would be great if we would have a standard assay or a way to look at these cells and see is there some if is there is this a patient where we have healthy T cells where we can recruit them and we can, help kill the myeloma cells?

So there are, you know, different markers on the surface of the T cells that can help decide are they fit or not. So basically the markers that show that either the T cells are naive phenotype or memory phenotype. You know there's Cd28 and you know there's various different markers on the surface of the T cells that indicate fitness.

And there are other markers of exhaustion, that can, you know, indicate that those T cells have already been over activated and, and are destined to, not survive very long.

Should we be checking markers of T cell fitness before T cell therapies? Are there any tests that we can do? There are a lot of research studies that have indicated that better T cell fitness, can improve outcomes after T cell therapy, whether it's CAR-T cells or bispecifics and markers of T cell exhaustion can indicate a higher risk of early relapse after car T cell therapy.

The problem is that right now, there's not really a commercially available test that most patients will be able to to run on their, T cells.

And it probably also changes over time. You know, it's really a function of what those T cells look like right on the day of the collection, probably.

Can exhausted T cells be reactivated?

So the next step, then, if we if we see these exhausted T cells, the question is, is there a way, and how can we get these T-cells out of this exhausted profile and into a more active state where we can actually recruit them and then use the bispecific antibodies.

So here at MSK, we're about to open a trial with a second drug that we can use first, which have shown to activate T cells. So we can activate the T-cells, stimulate the T cells, get them to proliferate to be more of them. So the trial is to start with one medication to prime the T cells to activate them and then give the bispecific antibodies to then hopefully have this synergistic effect of both the stimulating effect and then come in with the T-cell, engaging therapies to have a high treatment response when we, when we kill the myeloma cells.

What strategies are being explored to avoid using exhausted T cells?

We are trying to do studies now where we collect those T cells before patients start therapy.

For example, in the CARTITUDE-6 and some groups of the CARTITUDE-2 studies, we're actually collecting those T cells before they start their induction therapy to see if that makes any difference on having more fit T cells and, longer lasting T cells, I think it is going to be important. It is something that we'll probably be measuring down the road, but it's not something that's widely available at the moment.

Using healthy or revitalized T cells could make T cell redirecting treatment stronger, longer lasting, and more effective. If you want to be able to participate in studies similar to what was mentioned in this video. Health Tree offers a free clinical trial finder.

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