What is being done to enhance the response of Car-T cell therapy and bispecific antibody therapy.

So, you know, Car-T cell therapy and bispecific antibodies have certainly transformed how we treat patients with heavily pretreated myeloma who have relapsed many times over. but we know that these therapies are not curative in that group of patients. And sometimes the remissions can be short, particularly those with higher risk disease. So we certainly want to better understand why some patients have durable responses to these therapies and why others do not, and how we can, make these, therapies perform better for all of our patients.

So there is a lot of interest in the immune microenvironment, you know, in, you know, these therapies.

The immune microenvironment is a complex system of cells and substances that can promote or suppress the immune system's ability to fight cancer.

Immune checkpoint inhibitors take the brakes off the immune system, allowing the immune system to recognize and attack cancer cells.

So immune checkpoint inhibitors, like you mentioned, I think are one area of investigation. Now, the immune checkpoint inhibitors have a checkered past in myeloma studies. So I think there's a little bit of trepidation, with these agents.

Studies using the checkpoint inhibitor Keytruda in myeloma were stopped due to increased number of adverse events in the study arm.

but, you know, we're using these in a very different manner when we're combining them with bispecific antibodies as well as Car T-cell therapy.

So, there are ongoing studies looking at PD1, Pd-l1, immune checkpoint inhibitors combined with bispecific antibodies. For example, at Levine Cancer Institute, we're looking at nivolumab for just a couple of doses after ide-cel Car T-cell therapy to see if we can improve expansion of the car T cells and persistence of the Car-T cells and get more durable results, after ide-cel.

And there are other factors, that limit Car T-cell function, other immune checkpoint inhibitors that will be, tested in the months and years ahead. There are other factors in the marrow microenvironment or in the tumor microenvironment that can suppress the manner in which, T cells activate.

A good example of this, there's a molecule called adenosine.

When present at very high levels in the tumor, micro environment that can kind of paralyze functionality of T cells. And there's an oral drug that's currently being developed that inhibits the production of adenosine in the tumor microenvironment.

So the question you know, we want to ask obviously is if we inhibit the production of adenosine in the tumor microenvironment, can car T cell therapy and bispecific antibody therapy perform better.

So lots of very interesting things going on both at the benchtop level but as well as in early clinical trials.

What are immune checkpoints?

The interaction of white blood cells, with cancer cells is highly intricate.

And there are signals that can be produced by the cancer cells that will tell, the immune system to stand down.

So when we talk about, checkpoint inhibitors, so immune checkpoints are proteins that can be expressed either on the T cells themselves or on the cancer cells that basically tell the T cells to stand down.

You know, and this, you know, process has a physiologic purpose. So, you know, we need a functioning immune system to fight off infection, to fight off cancers, for example.

But we can't have too overactive of immune system where we start developing autoimmune diseases and what have you. So there's this very delicate balance that's required as far as immune function is concerned.

And cancer cells can take advantage of that and can again, liberate factors that will tell those T cells to stand down.

And there's a number of them that have been identified. You know, we talked about PD1, Pd-l1, there's something called lag three. There's something called TIGIT, there's something called a TGF beta in the tumor microenvironment that can cause T cells to function less well. We talked about adenosine.

So there's all of these things, that can be present in and around, you know, those cancer cells that will impair the ability of the car T cell or bispecific antibody to do what it's doing,

The car T cells may still bind attached to the myeloma cell. But if all these signals are being liberated in the, in the in the immune microenvironment, telling it not to activate, not to kill, that's a problem.

And we just need to better understand the mechanisms behind that and how we can overcome that.

So CAR-Ts are without a doubt very powerful transformative therapies. however, there's still some room for improvement. certainly there's room for improvement in the toxicity. as we, I'll have discussed the, you know, the risk of CRS and ICANS and so forth, but also in the efficacy, because it appears that, the majority, if not all patients eventually experience a relapse, particularly when those drugs are used in the relapsed refractory setting.

And I think a few things are being pursued to try to enhance the activity of their Car-Ts.

One of them is as maintenance therapy, which is a little bit controversial because, you know, it makes biological sense, but it kills one of the greatest advantage of this therapy, which is to have a treatment free interval. But nevertheless, things are being pursued including the use of CelMods which are drugs that are evolutions of the immunomodulatory agents.

I mean, many of you may have heard about iberdomide or mezigdomide, and those drugs have a potent effect on the myeloma cell, but also in the immune system, and could enhance the activity of the CAR-Ts.

Other things that are being pursued as maintenance therapy are bispecific T-cell engagers of a different target, trying to hit quote unquote, two targets at the same time.

and yet other approaches are drugs that can modify the body's immune response, something that's called, that, we call, checkpoint inhibitors, things that kind of take the brakes off the immune system, and it could make those T-cells eventually work better.

Other source of, potential improvement comes from the Car-T cells themselves. you know, some Car-Ts in development actually go after not one, but two targets.

We have seen preliminary data of, Car-T that target both BCmA and another protein called Cd19 that can be expressed in early, early cells that grow towards myeloma, also we have in clinical trial a Car T-cell the target simultaneously BCmA and GPRC5D which are two targets that we know are successful against a successful, meaningful targets for immunotherapy in myeloma.

There are other approaches, like third and fourth generation, CAR-Ts that have some technical enhancements that make them they can make them more potent.

As well was the idea of allogenic CAR-Ts, which might make them more efficient, but also remove some of the barriers that patients have to receive Car-T now, by being able to have an off the shelf universal donor product that can be deployed, in a short period of time.

What are fast car T cells?

Fast Car-T is a term that has been used for CAR-Ts that have a faster manufacturing process.

And that would address one of the main barriers, for Car-T, which is, you know, the time that takes between the decision being made to proceed Car-T and actually receiving the infusion. And a lot of the time is consuming with manufacturing.

So if you have a faster manufacturing process, you can substantially, cut off that time. And some of the constructs that, that have been developed with that property also seems perhaps to be more active. So there's certainly room for improvement there.