Research Updates From ASH | Myeloma CAR T-Cell Therapy

Transcript

Laura Beth Ezzell:

We appreciate you taking time out of your day to join us. And before we get into the discussion, I’d like to just start by discussing your role as a researcher.  

You play a pivotal role in moving myeloma care forward. So, what inspired your work in this field?  

Dr. Ciara Freeman:

It’s a great question. It’s something that I’ve been passionate about for quite some time. Myeloma is a disease where innovation really changes lives. When I first started out learning about hematology and blood cancers as a student, myeloma patients had a very dismal prognosis. 

And there has not been more innovation, I would say, in any cancer field that has been more impressive over the last number of years than in the setting of multiple myeloma. We’ve seen more drug approvals. We’ve seen greater advancements. Early in my training, I’d seen patients who’d exhausted every available option, but the biology sort of suggested to us that the immune system still had this tremendous untapped potential, and we’re really just seeing that now.  

We’ve seen incredible developments in CAR T-cell therapy, where basically, we take a patient’s own immune cells out, engineer them, and then put them back in the patient’s body to recognize, and seek and destroy, and kill those cancers.  

And it’s no longer experimental. It’s now becoming a core pillar of what we do. And so, it’s been something I’ve committed to ever since, helping translate that promise into durable, real-world benefit for patients.  

Laura Beth Ezzell:

Yeah, so interesting, and thank you for setting that up for us. We’re on the heels of the annual meeting of the American Society of Hematology, where blood cancer researchers from around the world come together to share their research. So, can you start by sharing maybe some of the highlights from that meeting, particularly relating to CAR T-cell therapy?  

Dr. Ciara Freeman:

Absolutely. Again, I said, CAR T-cell therapy is no longer experimental. It’s a real, core pillar of what we’re doing now. We’ve seen ongoing deep responses from some of the approved CAR-T cells that have already come through and have FDA approvals, even in heavily pretreated patients.  

We’ve seen more data come through in earlier line use, suggesting that patients who get treated earlier probably have better durability when it’s used earlier in the disease course. We’re seeing great momentum around dual targeting, so targeting more than one marker on the surface of the cells. We’ve seen next-generation constructs trying to prevent relapse.  

And, of course, we’ve got a huge input here from our own real-world data. We’ve seen an incredible amount of data coming out from the consortium that we are a part of at Moffitt, led by Dr. Hansen, looking at real world outcomes; toxicity, mitigation, and patient selection.  

So, the field is really moving from “Can this work?” to “How do we make it better, safer, more durable, and really get it out to more and more patients?”  

Laura Beth Ezzell:

Let’s talk about next-generation CAR T. So, what’s coming down the pipeline, and how are these different from currently approved CAR T-cell therapy? 

Dr. Ciara Freeman:

So, we’re seeing novel targets. So, certainly we’re seeing CARs being developed that are going after a different marker. So, for example, we presented data from a trial in progress of a GPRC5D targeting CAR. That’s a very painful, long-winded name for a target, but essentially it’s a different target to the one that is currently being exploited with everything else that’s been approved with the exception of a bispecific.  

So, that trial is specifically enrolling patients who have failed all of the tools in our toolbox, including a BCMA-directed therapy. So, we’re definitely seeing novel targets under evaluation, and that trial is a pivotal trial, and we’re recruiting at Moffitt right now. We’re seeing dual-targeting CARs. So, pairing BCMA with another target, to try and reduce this theory of what’s called antigen escape.  

So, basically where the myeloma cells can evade by hiding one target, and having another one there, means that the CARs have two opportunities to basically attach and kill. So, doubling your money, if you will, like betting on two horses rather than one. We’re also seeing armored CARs come through. So, they’re designed to basically resist the suppressive environment around them.  

So, you can imagine sending your recruits in with more weapons, to sort of get things out of their way. We’re definitely we’re seeing more data on how we can improve T-cell fitness and persistence. So, one of those things is obviously to get the recruits out earlier, to use the T cells earlier, but there are also manufacturing techniques that have been explored, how we can basically manipulate that in a manufacturing point of view. And then, the other thing was very exciting at ASH, seeing off-the-shelf therapies. So, one of the late-breaking that came out at the ASH meeting was an in-vivo CAR. 

So, a CAR where instead of sending the recruits off to bootcamp, you host the bootcamp in the patient’s body. So, that was a very exciting, obviously, very small data set very early, but making the whole process much more streamlined and efficient, and also eliminating the need for the chemotherapy that we give before we put the SEALs in. All of that would be if we can show that this is a successful approach. That will totally change our current delivery paradigm. It will be very exciting for patients.  

Laura Beth Ezzell:

Yeah, absolutely. That sounds very promising there. And, Dr. Freeman, can you talk about the advances in manufacturing T cells?  

Dr. Ciara Freeman:

Yeah. So, that’s obviously another area where we can improve things. So, how fast the cells get turned around has not only got an impact on the patient experience, because obviously if a patient has to wait a very long time, there’s a chance that we could lose disease control while we’re waiting for the cells to get made. So, those SEALs have got to get made quickly. 

But we also don’t want them to get too flogged at bootcamp, so that by the time we put them back in to seek and destroy, that they’re exhausted. And so, what we’re seeing is manufacturing that is faster, more consistent, and trying to sort of optimize the T-cell quality to preserve the younger, more kind of what’s called naïve cells, and also reduce variability. So, having a more consistent product delivered for patients. These are all key steps towards broader access and better outcomes.