What factors should be considered when choosing between a car T cell therapy and a bispecific antibody therapy?

How do you sequence them?

Currently, we only have one bispecific antibody which have started getting the B-cell maturation antigen or BCMA as a target on myeloma cells.

It's called teclistamab,, but we have many other bispecifics that are coming, you know, down the pike for regulatory approval in the United States. So we have two CAR-T cell therapies and one bispecific all targeting the same thing. I think the real question here is, you know, which patients are eligible for CAR-T cell therapy based on their performance status.

You know, if it was up to us, you know, all our patients would be getting CAR-T cell therapy because of the advantage that you can give cars. And then patients are not on any maintenance treatment. They recover quickly and have a good quality of life. However, in reality, we can only give car-ts to, you know, only a small number of patients.

This is where bispecifics have been very helpful in getting BCMA directed treatment to patients who need it the most, and we're learning how to use them best. So you know, for patients who are responding to the bispecifics, unlike how they've been studied in clinical trials or being given more frequently, we're giving them less frequently to reduce their risk of side effects or infections.

So, you know, the number of CAR-T cell therapy procedures, you know, every center can do, you know, has has a limit right now. And that limit had been related to the number of slots that the centers are able to get from the sponsors.

However, there's also a capacity issue at each of the centers. You know, there are so only so many transplant or cellular therapy procedures any center can do because of, you know, chair availability, you know, collection procedure availability and staffing.

those are very important considerations, you know, and of course, you know, you have to keep in mind patients preference as well as the trajectory of their disease.

If the disease is moving very rapidly and they need treatment right away and they won't be able to, you know, have the disease control until they can get CAR-T, it's better to, you know, offer a bispecific treatment as an option for them.

There's a big debate currently about, the difference and the efficacy of car T cells and bispecific antibodies, both of which engage the same process, which is T-cell engaging therapy.

So T-cell engaging therapies are very powerful, probably the most powerful tools we've ever had.

And we're in the process of learning how to use them in the most appropriate, way for patients. So in this setting, it's not just the mechanism of action and the biology of the therapy, it's the political process that's going on at the same time, in terms of can you manufacture Car-T cell therapies efficiently?

Can you get them to the patient in a prompt enough time without having to do bridging therapy? And so how does all of that really rather complicated approach play out in the context of a bispecific antibody, which is basically off the shelf, doesn't need all of that, complexity and has an efficacy that is somewhat similar.

And so while people claim to think that CAR-Ts are better or Bispecifics are better, there's not a direct head to head comparison. There probably never will be.

Possibly the CAR-Ts look more efficacious, but like I say, the choice is not straightforward. I think we know that giving a bispecific before a Car-T in that setting, the CAR-Ts are somewhat less efficacious than if they'd been given the other way around. And so I think that's the clue about how you might sequence the agents.

Further. It's not just about the mechanism of action. It's about the target that you use. And so there are a number of, drugs targeted against BCMA, which is the commonest, most widely used. There are drugs targeted against GPRC5D and then drugs targeted against FcRH5. and so we have different targets. And so which target should you go for.

And so again BCMA is the most commonly used. there are issues with resistance to the drug. And what's driving resistance is not failure of the T cells. Often it can be mutations and loss of the target.

So if you lose the BCMA target, you’re not going to be able to target something else against it.

So it looks like we'll be using drugs targeted against BCMA, then following up with a drug targeted against GPRC5D and vice versa.

it looks as if GPRC5D, because it's sort of a dispensable target, may be lost by the cancer cells somewhat more easily than BCMA. So while I think we have hints currently, I think as time goes on, we're going to have more certainty and I think we'll have molecular diagnostic tests looking for the target mutation in the target and will work out an optimum way of, sequencing these drugs.

But for now, I think if you can get one of these drugs, you take what you can get, go for it. And I'm sure you will do well with what you've given

So the question is when we're thinking about using bispecifics and Car-T cells, the one of sequencing and this is a huge discussion within the myeloma investigator community.

so we do know that if a patient had prior BCMA therapy, they can benefit from other BCMA therapies. But we think the likelihood of benefit is somewhat lower, and that's probably twofold.

One is that if we are targeting BCMA with teclistamab and then the patient benefited and then stopped benefiting, one of the ways that cancer cells, myeloma cells will escape is by getting rid of the target, getting rid of BCMA. And so if the cells don't have any BCMA, then a car T cell is not going to be effective.

the other thing that happens is that sometimes because we need T cells both for bispecific antibodies as well as for Car-T cells, sometimes the T cells are no longer functional. and so if the T cells aren't functional then, another T cell directed therapy is not going to be effective.

I think most people from a sequencing standpoint, would if it's possible, would sequence the Car-T cell first and then the bispecific later.

And the reason is, is Car-T cells a one time therapy and the relapse after car-t cell is less likely to be associated with loss of the target, whereas the relapse with bispecifics is more likely to be associated with loss of the target.