EMN 2021 | Targeting BCMA for R/R myeloma

In order for an immunotherapy strategy to be effective, you’ve got to direct the immune system to a target. And in myeloma, we have, for many years, been struggling with a defined target that will allow you to redirect the immune system towards. And more recently, the B-cell maturation antigen, or BCMA as it’s called, was found to be highly expressed on malignant plasma cells by comparison to the normal plasma cell population, which is an important differentiation, because you don’t want to take care of your normal plasma cells, because then you induce therapy-related hypogammaglobulinemia. But also, it’s important that the target is also now expressed on the B-cell lineage as well, because that again gives rise to secondary humoral immune defects.

So, BCMA is highly expressed on malignant plasma cells. So, it lends itself to become an immune target. And there’s quite a lot of biological issues there about heterodimerization, of promiscuity of receptors ligands, which is probably best not to go into at the moment.

But let’s just concentrate on BCMA as a target. So, you can develop a monoclonal antibody that’s naked. By that I mean there is nothing on the end. It will attach to the BCMA, and the naked end will stimulate the natural immune response. It will generate complement fixation, potentially. It will generate the phagocytic sense system to engulf the coated cell. It will engender cytotoxic T lymphocytes to attack and engage. So, that’s what the naked antibody does. And, depending on the subclass of antibody, the monoclonal antibody, depends on how much of each of these domains is the mode of action. And naked BCMA antibodies are in clinical trials development.

But, perhaps more relevant, is to put a payload on the end. So, what you do is you attach a cytotoxic, that otherwise, if you give it systemically may have too many side effects that makes it difficult to tolerate. But, if you put it onto an antibody, the antibody draws it to the tumor cell, and then, either, once it’s in the tumor microenvironment there, the payload attaches, or the antibody is internalized, and it’s then detached. So, you actually get local cytotoxic delivery.

And it’s a strategy that has been around for a while. So, to come back to the BCMA-directed strategy, belantamab mafodotin, or bela maf for short, is just one of those antibodies that is directed against BCMA. It will then bring up the mafodotin moiety, which is the cytotoxic. The antibody complex is internalized. The cytotoxic dissociates and then delivers intracellular cytotoxicity and killing. And the company who have this as a product, have been proceeding through their clinical development program to get bela maf monotherapy accepted by the regulatory authorities. But, at the same time, exploring, what role adding it to combined therapies, including back bones, such as lenalidomide, dexamethasone, pomalidomide, proteasome inhibitors, like ixazomib, et cetera, et cetera, and you can couple up with other antibodies.

Now in the UK, Rakesh Popat has been leading a very novel early phase study. It’s a platform study. So, this is where we have multiple Phase I/II cohorts where we have the control, if you want to call it that, as bela maf monotherapy, but then we are opening cohorts where we are adding cyclophosphamide and dexamethasone to this antibody, ADC, antibody-directed cytotoxicity. So, we add cyclophosphamide-dex to the ADC, or we’re going to add the ixazomib-dexamethasone to the ADC. And it’s building up, layering up the impact on top of this immunotherapy strategy. That’s one way to go, but our other strategies are in that nature. So, that’s in the ADC, so an antibody with a payload.

Other ways of attacking the BCMA, everybody knows about them, CAR T-cells. And this is where you effectively rewire genetically a T-cell, so that it will stick to BCMA, because T-cells are not naturally generated to attack BCMA, because it’s not an antigen, a foreign antigen. So, what you do is you give the CAR T-cell an artificial T-cell receptor that is designed to attach on to, in this case, BCMA. The T-cell approximates to the tumor cell. It engages with the BCMA. It becomes activated as a consequence of this man-made T-cell receptor, because of the internal signaling motifs on that receptor. And that T-cell becomes activated and kills the tumor cell.

And we’ve seen some really impressive depths of responses with CAR T-cells. Most of which, and so far in myeloma, have been directed against BCMA. Problem is though that while we are getting real impressive depth of response in advanced disease, some of these people going into the trials have had like six lines of therapy, et cetera, it’s not lasting. There is a measurable PFS. So, as a cure in myeloma, unlike diffuse large B-cell, in myeloma it’s not there yet, but it may be that we need to tweak the technology or combine technologies in order to get that. But it’s another example of a BCMA-directed immunotherapy strategy.

Now, the third class is called T-cell redirection therapy or bispecific T-cell engagers, or BiTEs for short. And, basically, what these are, are man-made molecules that are effectively an antibody directed against BCMA and an antibody directed against a T-cell marker called CD3, and these two antibodies are stuck together. And the different BiTEs of dual bodies, are another name for them, have different chemical compositions, but basically that’s what they are. They are two antibodies stuck together, and what they do is they form a bridge between the tumor cell and the T-cell. And as you proximate that T-cell, like you proximate the CAR T-cell to the tumor cell, once they are approximated, they’re switched on, and again to killing mode.

Now, BiTEs, unlike CAR T-cells, are off-the-shelf. They’re in a bottle, you give them to patients, initially IV, a lot of the BiTEs are now being investigated to be subcutaneous, but you don’t need to manufacture a patient-specific entities, which CAR T-cells currently are. Although there’s some interesting data about allogeneic CAR T-cells, a topic for another occasion, perhaps. But the BiTEs they can be given, and they can actually stimulate the immune system. The same advantage of BiTEs is that they aren’t relying on one T-cell clone that you’ve generated. They’re relying on all the T-cell clones that you can switch on in the person so that there’s a potential there.

But, of course, the big elephant in the room about immunotherapy and myeloma, is that the immune system in myeloma is particularly compromised at diagnosis, and with advancing stages of disease and recurring rounds of treatment, that immune system doesn’t get any better.

So, you are looking to, say CAR T-cells, taking those T-cells out. They’re already exhausted. They already will show evidence of immunosenescence. They art dysfunctional. You’re trying to rewire them, put them back in and expect them to behave like a T-cell from a normal, healthy person. Similarly, you put a BiTE in there, you’re coupling up T-cells that are exhausted and senescent, and you’re trying to get them to do a job that they’re maybe no longer capable of doing. So, CAR T-cells don’t last very long, which is why you’ve got this measurable PFS. With BiTEs, the danger that you could drive an already exhausted, senescent population to become more exhausted and more senescent.

So, there are issues about the fundamental tumor immunology going on in myeloma at that point. But those are four areas where BCMA could be targeted. Naked monoclonal antibodies, the lights, all the daratumumab light, well daratumumab doesn’t attack BCMA, it attacks CD38, but that’s an example of a naked antibody. You can have a payload or an ADC or bela maf, or belantamab mafodotin, is an example. There are CAR T-cells that are rewired T-cells towards BCMA. And ide-cel and cilta-cel are two very advanced products that are getting regulatory approval and getting into the clinic. And then you have BiTEs. Now, there were seven different BiTEs presented as new data at ASH, five of which were BCMA-directed. So, it’s an evolving field in BCMA.

One last thing to say about BCMA in terms of a target, is that people relapse after they’ve had BCMA-directed therapy. And why may that be? Well, I’ve already mentioned immune reasons why. So, the T-cells may get more exhausted, may become senescent, may not work. But there is some really interesting, what has been presented, and Nikhil Munshi’s group from Boston, presented a paper last week, week before, and him and Einsele and Leo Rasche from Würzburg also published a really nice paper in Nature Medicine, that looked at actually myeloma cells losing the expression of BCMA as a potential explanation for developing resistance. Not so much not responding first time around, but losing it as you get clonal evolution, then you’re getting biallelic deletions of the BCMA-producing gene. And, therefore, the tumor cells lose BCMA expression. And if they haven’t got BCMA on, all of these strategies are not going to work. So, we are starting to understand a bit more about the immunophysiology of BCMA in this context going forward.