What ways are being explored to revitalize exhausted t-cells?

What ways are being explored to revitalize exhausted T cells.

how do we make t cells work? Better or less exhausted? You know, it really depends on are we talking about CAR-T cells or your natural T cells. One of the things that we're doing in practice, let's say a patient gets CAR-T cell therapy and they're not as effective as we had hoped or they're not in a complete remission.

Many of those patients we’re putting them on immunomodulatory drugs like lenalidomide or pomalidomide after the CAR-T cell therapy to try to improe their response or the durability of their t cell function. And that can potentially help activate those T cells. You know, the IMiDs get their name for immunomodulatory because they have activity on the T cells and so that's one option.

And there are actually several trial clinical trials right now looking at specifically priming the T cells with these immunomodulatory drugs and then keeping them on them after the infusion. Right now it's not a standard practice, but it you know, many of us are using those also potentially checkpoint inhibitors, which are monoclonal antibodies that help kind of decloak the tumor cells and help them be recognized better by the T cells and help T cells function better in that way.

Those are being used in many different cancers. There's some at least anecdotal evidence or case reports of these being effective after CAR-T cell therapy to try to reawaken the response of the the chimeric antigen receptor T cells. But I think the key is going to be eventually, you know, doing these T cell therapies earlier in the course of disease.

Right now, they're approved for patients who have had four prior lines of therapy. There is data that shows that these cell therapies and t cell redirection therapies are potentially very effective after one or two relapses. We're hoping that these can eventually get approved for earlier lines of therapy, where I think using more functional or healthier T cells that have not been not been exposed to many years of therapy might be helpful.

On April 5th, 2024, the FDA approved new indications for both CARVYKTI and ABECMA. The FDA approved CARVIKTY for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and who are refractory to lenalidomide.

The FDA approved ABECMA for the treatment of adult patients with relapsed or refractory multiple myeloma after two or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, and an anti Cd38 monoclonal antibody.

Talvey and Elrexfio received FDA approval in August 2023 for myeloma patients who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti Cd38 monoclonal antibody.

We don't really have a mechanism yet, though, of, you know, just collecting and storing T cells for patients that one would think that might be a useful we don't really have storage facilities or insurance coverage or anything like that for just randomly collecting T cells earlier in the course of disease. But I think eventually that may be key is getting these T cells and training them to recognize the myeloma.

Before the patients had a decade of therapy

Can t cells from a donor be used?

Can we use someone else's T cells? So there are several trials ongoing looking at allogeneic CAR-T cells, for example, that have had been have been gene modified to prevent them from attacking the patient and from being rejected by the patient.

You know, a few different companies are looking at this. And so it's very exciting.

And, you know, there's some preliminary data that looks good, but we don't really have long term follow up and certainly nothing approved right now for using allogeneic CAR-T cells. But, you know, those would be off the shelf. Then we wouldn't have the month long production delays that we have for patients that are using their own T cells.

So, you know, I think down the road those are going to be very important.

What happens if you give T-cells a break from therapy?

the one been biggest benefit of CAR-T cell therapy is these patients are off therapy as long as they're in remission. So their T cells are free from ongoing. You know, treatment with chemotherapy and steroids. And so potentially those cells that are in there after that point can be accessible for reawakening or reactivation.

And for example, patients that have had alkylator therapy prior to their t cell collection have worse outcomes, probably because those alkylator therapies are really effective at depleting T cells or making the T cells more dysfunctional and just giving them a period of time off of those therapies is probably beneficial to be able to collect more functional T cells.

And the same issue we're having with prior BCMA directed therapy before CAR-T that seems to be detrimental for the outcomes after CAR-T Cell therapy if they've had any other BCMA directed therapy, most notably if they've had prior bispecific t cell therapy or antibody drug conjugate therapy, those patients had significantly impaired progression free survival after CAR-T, But the question is how long of a washout do we need?

How long do we need to be off these things before it can allow a better t cell harvest or a more functional t cell product? Other studies now are looking at saving those until after the collection and then giving other T cell therapies to bridge the patient to CAR-T. But right now it's not standard.

I think that's going to be the next big frontier now that we have so many available t cell therapies, we have five of them that we know that we likely can't just give one after another like we have done historically with some of the myeloma therapies because of this reason of t cell exhaustion. So you have a twofold problem.

You have the antigen that you're targeting on the myeloma cell. Many of these new therapies target the same antigen. So eventually there could be mutations around that antigen that can then block the effects of some of these therapies or a complete loss of some of those antigens in some patients. So that's one issue. But the other issue is the T cell end of it, right?

So you can have the antigen still present and then you keep giving these therapies and patients are not going to respond because the T cells no longer have that phenotype that's actually going to attack the myeloma cells.

So I think we're at the infancy of figuring that out. But we do have certain markers on these T cells that can be studied.

Right now they're at a research level for us to try to understand when the phenotype shifted from kind of the more attacking T cell version to a more exhausted version. And then can we look at modifying that therapy before that happens or right when that happens? And I think right now the way to do that is going to be giving it less frequently.

So you know, these bispecific antibodies are approved in a very continuous open ended weekly basis in some circumstances. And I think the first step is going to be figuring out when that happens. And then perhaps not giving it as frequently for patients that are in a good response, especially. So I think more to come on this topic. I think going to hear a lot more over the next few years.

But right now, you know, that's where we are with with the current available data. we're still figuring out why some patients have more exhausted T cells or who has more exhausted T cells and how we could improve it.

But we do know that t cell directing therapies need you to have good T cells to actually have the efficacy of the therapies.

Some of the ways that, you know, has been done in the past is immune checkpoint inhibitors like pembrolizumab or nivolumab. These drugs are actually targeting proteins that are related to T-cell exhaustion. So they are working in that mechanism.

However, in myeloma, we haven't seen that much improvement or responses with these therapies. So we don't really use them often.

But that one, way of changing, you know, the T-cell phenotype. Another, we could be looking at the, you know, immune modulating properties of like lenalidomide or these would be drug ways.

The lifestyle could be another thing like physical activity is known to improve you know immune the immune system so is diet and the microbiome.

as we learn more about these areas and research it, I think that could be an opportunity for lifestyle to improve response rates for myeloma patients in immune therapies.