How Has Myeloma CAR T-Cell Therapy Changed in Recent Years?

Transcript

Laura Beth Ezzell:

So, how does CAR T-cell therapy actually work?  

Dr. Ciara Freeman:

So, how I usually describe it to my patients is their own immune system has ignored the cancer that’s living there. It’s for some reason. I say that the cancer put on some glasses with the little funny mustache, and it’s hiding from them. And so, what we’re doing is we’re sort of refocusing the immune system back onto the cancer, to kill and destroy.  

So, in the setting of CAR T-cell therapy, what we’re doing is we’re taking out what I call them the basic recruits.  

So, the patients own T cells that reside in their body, and we send them off to bootcamp; and we send them off to bootcamp to turn into Navy SEALs. And how that happens is they’re basically genetically engineered to express on their surface something that recognizes the cancer cell when it meets it.  

And a signaling piece that goes into the cell and says, “When you meet this thing, you get all jazzed up, and you attack like crazy.” And so, that’s the sort of basic loop. 

We send the basic recruits off; they get manufactured into a little army of cancer-killing machines; and then, we get the patient back; we make sure that they’re fit and ready and all primed to receive these little armies; and we put the cells back in the patient’s body, to seek and destroy. And that is somewhat complicated, and sort of a process that isn’t available on everyone’s doorstep.  

So, it’s really something that’s primarily been focused on centers like Moffitt, where we have all the capabilities to really manage patients well. But we’re working hard to sort of make that process as efficient, and streamlined, and effective as we possibly can.  

And we know that once you put that little army back in, it has outperformed standardized approaches with combination chemotherapy regimens in trials, head to head, over and over again, we saw updated data; overall survival benefits for patients who got CAR T in earlier lines of therapy compared to standard of care. So, it’s an exciting space. It’s definitely something that we want to build upon and grow for our patients. 

Laura Beth Ezzell:

Okay. I love that explanation. I can totally picture the Navy SEALs there. So, I think that’s a great way to explain that to your patients. And can you share, maybe, how CAR T has changed over the last few years?  

Dr. Ciara Freeman:

It’s definitely evolving. Certainly, from work we’ve done, when we first had CAR Ts in our hands, the first approval came through in 2021 for multiple myeloma patients. We were treating patients who’d really exhausted every single tool we had in our toolbox. Some of the patients we had coming forward for CAR T-cell therapy had been on therapy almost continuously for over a decade.  

Some of them had had a median of like six prior lines of therapy. Some of them had 12, 13, 14 prior lines of therapy. So, the idea that they would come and have this treatment, and be off treatment for the first time in a decade, was sort of life-changing for them. Regardless, I think what’s important is to really manage the patients well.  

So, I think what has really come through for us is our ability to identify patients in an earlier treatment line, ideally sequence things in such a way that we’re using CAR T earlier than we were previously, because now we can. We’ve seen FDA approvals come through in earlier treatment lines. Similarly, we’ve got trials open in earlier treatment lines, where we’re exploring this, so that we’re basically taking the patient’s own immune cells out at a point where they’re not so beaten up.  

So, you don’t want to send off tired, exhausted recruits who’ve been in the war for years and years and years fighting a battle, to then become Navy SEALs. What you want is those youthful, fresh, ready-to-go recruits to go off and become SEALs in bootcamp. So, I think that that’s been something we’ve learned a lot.  

The other thing we’ve learned is how to manage the enemy. So, what’s come out, has been really important, is having a patient who’s been what’s called bridged. And what that means is their disease is well-controlled, in between that period where we take the SEALs out, or we take the recruits out and we send them off, and we get them back.  

And in that window between cells gone and cells back, that we manage the disease that the patient has very well. So, that’s called bridging therapy, the bridge to CAR T. And I think what we’ve learned is that, you know, patients who were a better bridge, who got low disease burden on the way in, tend to have better outcomes. They’ve got less side effects. They respond better. They’ve got greater depth and durability response.  

And again, how I explain that to patients is, if you’ve got less enemies to overcome, those SEALs have got an easy mission. They just go in, seek and destroy, very little fallout. You’re not setting the whole town on fire. So, that’s sort of how I explain it to them, is it’s important to do those things. And then, we’re also managing the aftercare much better.  

So, we’re watching out for infectious complications. We’re watching out for risk of other things. So, I think we’re overall doing a lot better in terms of how we’re managing patients.  

Laura Beth Ezzell:

Yeah, and maybe just to add onto that, maybe a little more, what do you think researchers have learned from treating and monitoring like thousands of patients after this point, after they’ve received this therapy? 

Dr. Ciara Freeman: 

I think there are a lot of things that have come out; as I said, things that are important, using them earlier, using them first, if we can. So, there are other agents that are coming onstream, such as bispecific antibodies, which for people who are not familiar, they’re an antibody that has one end that attaches to the cancer cell, and one end that attaches to the immune cell, and it brings them together.  

And what we know is that if patients are exposed to continuous bispecifics, that is basically getting their recruits to do a lot of work, week after week after week. And then, you try and make CAR-T cells with the same target after that; they tend not to respond as well, because to some extent, the recruits are tired, and they’re not ready to become Navy SEALs. They’re exhausted at bootcamp.  

The other thing is that it seems to be that after continuous use of a bispecific, the target itself can change, and that happens more frequently in patients who get continuous bispecifics than patients who get CAR T.  

And so, our sort of mantra here at Moffitt is, if the patient is eligible for CAR T, we should try and do that first; and a lot of that came out from real-world data, that the sequencing matters. And so, if we can, we offer a patient CAR T-cell therapy first, either FDA-approved or on clinical trial, and we hold the bispecifics if we can, for later use.  

And that, in our view, at least as of right now, may well offer the patient a longer trajectory, such that if and when the CAR T eventually stops working, we have the bispecifics that are still ready for us to use, and there’s a lot of evidence to suggest that patients will still respond well and get more durability if we do it in that way than the other way around.