Tag Archive for: NK cells

What CAR T Research Is Ongoing to Improve Treatment Response?

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What CAR T Research Is Ongoing to Improve Treatment Response? from Patient Empowerment Network on Vimeo.

 How can CAR T treatment response be improved with research? Expert Dr. Krina Patel from The University of Texas MD Anderson Cancer Center discusses the CARTITUDE, KARMMA-9, and LEGEND studies and proactive patient advice about bispecific therapy and CAR T.

[ACT[IVATION TIP

“…before you start bispecific therapy, talk to your doctor about CAR T. And the reason I say that is that when you get a bispecific therapy, and currently that is not a fixed duration therapy, it is a continuous therapy. So patients are on it until they relapse. And the problem is that once you relapse on that T-cell therapy, your risk of losing BCMA, losing the antigen is much higher. There are mutations that we’re seeing that most patients get.”

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Transcript:

Lisa Hatfield:

So, Dr. Patel, given the risk of relapse following initial CAR T therapy, what approaches are being investigated to enhance the persistence and durability of CAR T-cell responses in patients? I know there are a lot of theories out there saying things like antigen loss might be an issue, the loss of the target BCMA, T-cell exhaustion, the environment of the bone marrow, what of those theories are being investigated or looked at?

Dr. Krina Patel:

Yeah, I think without causing too many issues with why we think CAR T is so great, where it’s a one-and-done, right? That gives people this wonderful time off. In the relapsed/refractory setting, I think our goal is can we use CAR T to cure, right? That is the ultimate question. And, again, with cilta-cel (ciltacabtagene autoleucel) [Carvykti], with the original data from the LEGEND study, which was the original study in China, those patients had a little bit less therapy than CARTITUDE. However, there are about 15 percent of patients that are six years out from their CAR T still in remission, right?

And so that gives us a little bit of hope that maybe we’ll have a small tail and a small number of patients that are cured from our current CAR T approaches. But the question is, how do we now increase that tail and make it more like lymphoma? And then hopefully, 90, 100 percent of patients eventually, how can we, how can you get everyone cured? And so I think it comes down to myeloma is not the same for everybody, right? So you have our high-risk patients versus our standard-risk patients. And I think the strategies are going to be different for those two patient populations.

They already are in the way we treat patients with even induction therapy and maintenance and consolidation. We tend to be much more aggressive with folks who have high-risk disease versus those who don’t. And so, I think the biggest studies right now that are looking at this are really the combination studies. And so looking at CAR T followed by some type of maintenance, but fixed duration maintenance. So CARTITUDE 5 and 6 and KarMMa-9, these are all the studies of the BCMA CAR Ts in frontline. All of them will have maintenance afterwards, but it seems to be that they’re going to be two years of LEN maintenance and that’s it, nothing after that.

So LEN, lenalidomide (Revlimid), we know that it activates T cells. It activates other immune cells like NK cells in the body, even B cells. And so when you get cytokine release syndrome from the CAR T, you’re already making more of these immune cells and activating them. And now you’re going to have lenalidomide in there to kind of keep that going, right? And so that could help with this, not persistence of the CAR T itself, but persistence of better immune cells that can actually keep your myeloma down, right? So I think that’s one way.

The other way is some of the new therapies like CELMoDs. So these are sort of the newer version of lenalidomide and pomalidomide. They tend to have more immune effect than the other two drugs. So there’s studies looking at other CAR Ts, so a different target, right? So we talked about antigen loss. If you’ve lost BCMA, then what do we do?

Well, there’s other targets like GPRC5D. So a couple of the studies are looking at GPRC5D-CAR-T plus mezigdomide, which is one of the CELMoDs, or another arm is iberdomide, which is the other CELMoD, and looking at different doses without causing too many side effects, but still helping the T cell keep going, all kinds of things going on there. So those are some interesting studies.

And one of the cohorts, it’s actually using a GPRC5D-CAR-T with a BCMA bispecific after, that’s combinations. So now you’re targeting two different antigens and you’re using T cells in two different ways, right? And again, it’s fixed duration so that it’s not forever, but after a certain period, hopefully, we fix the bone marrow and we’ve killed enough myeloma that hopefully it won’t come back.

And so I think all of those are different strategies for the T-cell exhaustion to help with that, to hopefully keep from getting antigen loss, or if someone does have antigen loss, figuring out a way to go around it. And then the microenvironment I think is the biggest one, is how do we find cytokines and other things that can give us a bone marrow microenvironment that makes it really inhospitable for that myeloma to ever come back again.

So there are early Phase I studies looking at some of this, but I think down the line, that’s really what it will be, that once people go into their stringent CRs, MRD undetectable, now what can we do to keep that bone marrow from ever letting it grow again? And I think those are some interesting studies in the future.

Lisa Hatfield:

Okay. Thank you. So some patients are asked questions about the sequencing, and you’d mentioned different therapies. So I’ll ask this really quickly as follow-up, do you have any recommended or are there recommended sequencing of these different therapies like CAR T, then bispecifics, then CELMoDs, not all of them are FDA-approved at this point, but what are your thoughts on sequencing of those therapies?

Dr. Krina Patel:

So my activation tip here is that before you start bispecific therapy, talk to your doctor about CAR T. And the reason I say that is that when you get a bispecific therapy, and currently that is not a fixed duration therapy, it is a continuous therapy. So patients are on it until they relapse. And the problem is that once you relapse on that T-cell therapy, your risk of losing BCMA, losing the antigen is much higher. There are mutations that we’re seeing that most patients get.

So that means the next time we try to use a different BCMA therapy, there’s a big chance it’s not going to work. And we have small studies that show that, that people who get a bispecific, and then we try to go to CAR T for both CAR Ts that the response rates go down and the progression-free survival. So the months that patients get without, needing other therapy goes down for cilta-cel (ciltacabtagene autoleucel) [Carvykti], 33 months in CARTITUDE. It goes down to six months in CARTITUDE-2 where they did CAR T after prior BCMA therapy. That’s a huge drop.

In ide-cel, the real-world data, we saw that after bispecifics, you only get 2.8 months. If you get a CAR T, even though the response rates were still 70, 80 percent, it obviously there are clones that that BCMA isn’t there anymore that we can’t kill. And then it just grows back, right? The other way around, we actually see still a really good response because CAR T is a one-and-done, most of the time, you’re not going to lose BCMA.

So that let’s say a few years later, the myeloma was coming back. It usually has the same BCMA on there. So now I can use a bispecific. And yes, the PFS is still shorter than what you would see if you never had any BCMA therapy. It’s still in the realm of, almost a year, PFS though. So it’s much closer to what we see in the real world for bispecifics than the other way around for CAR T, it’s much, much lower. So we try to do CAR T first then bispecific, if possible. The other part is a T cell. So if you try to make T cells right after someone’s coming off of a bispecific, it is really hard to get T cells that are functional that then we can actually put a CAR into and make it work. So again, why, doing a CAR T first, and then a bispecific makes the most sense for the majority of our patients if they can do it that way.

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Updates in AML Treatment and Research From ASCO 2023

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Updates in AML Treatment and Research From ASCO 2023 from Patient Empowerment Network on Vimeo.

AML expert Dr. Omer Jamy shares highlights from the recent American Society of Clinical Oncology (ASCO) annual meeting, including an update on an immunotherapy agent showing promise as well as a vaccine therapy being studied for patients in a second remission.

Dr. Omer Jamy is a Leukemia and Bone Marrow Transplant Physician and Assistant Professor at the University of Alabama at Birmingham. Learn more about Dr. Omer Jamy.

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Transcript:

Dr. Omer Jamy:

My name is Omer Jamy, and I’m a leukemia and bone marrow transplant physician at the University of Alabama at Birmingham. And I’m really happy to be here today.  

Katherine Banwell:

Well, thank you. Dr. Jamy, the ASCO 2023 meeting just wrapped up recently. What were the highlights in AML research from that meeting? 

Dr. Omer Jamy:

Thank you. Yeah. There were several interesting studies in AML presented at ASCO this year. I’d like to highlight a couple of them in particular mainly because the focus on a novel mechanism of action, at least for patients with acute myeloid leukemia. And that mechanism of action being immunotherapy. So, we’re all aware that immunotherapy has had tremendous results in solid tumors.   

It’s making its way into hematological malignancies mainly lymphomas as well as B-cell ALL which is acute lymphoblastic leukemia. And we are trying to investigate it in patients with AML as well.  

And I think in that context there were a couple of abstracts which I thought were really interesting. The first one was actually presented by Dr. Anthony Stein and colleagues. Looking at a drug which is basically CD123 NK-cell engager.  

And I spent a little bit trying to explain what that is, but basically, it’s a drug which it harnesses the person’s immune system to fight the cancer basically. So, it targets an antigen which is expressed on leukemia cells called CD123. And it binds it to natural killer cells or NK cells. So, this drug is taking the host which is the patient’s natural killer cells and the leukemia cells and binding them together and then leads to the activation of the NK cells which causes killing of the leukemia cells.  

So, I think that mechanistically speaking that’s a very interesting concept to fine tune the person’s own immune system to fight the leukemia. This is obviously very early in development, so it’s a Phase I study, Phase I/Phase II. And they have presented results in 23 patients with relapsed/refractory AML.  

And just to give you some background, CD123 is expressed in the majority of patients with acute myeloid leukemia. It’s also expressed in patients with myelodysplastic syndrome as well as ALL. So, the study had all three diseases, but we’re going to focus on AML today. So, there were 23 patients with acute myeloid leukemia in the study. And because it’s a Phase I study, they have to test it at the lowest dose, and then assess for safety, and then keep on going up on the dose. So, they actually looked at six dose levels. And luckily because it’s a Phase I, the primary objective is to make sure it’s a safe drug to administer.  

And then second your objectives are basically if it’s efficacious or not. So, there were no dose limiting toxicities in the 21 evaluable patients out of the 23. So, that’s good. I think the lowest dose was 100 micrograms per kilograms per day. And the highest dose was 3,000 micrograms per kilogram per dose. The doses IV once or twice a week for the first couple of weeks, and then followed by weekly administration. In 23 patients the drug was thought to be safe. Again, no dose limiting toxicities.  

With immunotherapy you worry about side effects such as cytokine release syndrome because you are basically putting your immune system in overdrive. So, you don’t want to make sure your immune system doesn’t wreak havoc on the body itself. So, cytokine release syndrome or CRS as well as associated neurotoxicity are two common side effects of most of these novel immunotherapies.  

Which for the general audience, if they’ve heard about CAR T therapy or antibody drug conjugates or bispecifics, these are all under the same umbrella of immunotherapy. So, their side effect profile is pretty overlapping and different from what would be seen with conventional chemotherapy. So, they saw no neurotoxicity. And they saw CRS which was very manageable, right? Grade 1 or Grade 2 in a couple of patients. And as far as efficacy was concerned, out of the 23 patients they saw a response in three patients. Now that doesn’t sound very appealing, but you have to realize these are starting at a very low dose level and going up. So, when they looked at patients who were getting a dose of 1f,000 micrograms per kilograms per day, so a pretty hefty dose. Three out of eight patients, which roughly translates to 40% of the patients, achieved a remission. So, which to me for relapse refractory population is attractive. And it makes me want to investigate this molecule further.  

And that is exactly what’s going on currently with the study. And I think again CD123 is an interesting target. The other companies targeting as well either as NK-cell engagers or antibody drug conjugates with other payloads. So, this is an area of active investigation. So, that’s where – 

Katherine Banwell:

You said – 

Dr. Omer Jamy:

Yeah.  

Katherine Banwell:

Yeah, you said there was another study. Could you briefly tell us about that.  

Dr. Omer Jamy:

Exactly. So, the other study is also harnessing the person’s immune system to fight leukemia in a very different way. And this is a randomized Phase III study, ongoing. It’s international. And it’s a trials in progress meaning that it’s accruing across the country, or actually across the globe. And I wanted to highlight this in case people want to reach out to centers where this study is ongoing and want to participate in it. This is a trials in progress poster of a compound called GPS which is basically a vaccine against a protein called Wilm’s tumor 1 or WT1 which is vitally expressed on leukemia cells as well.  

Now this is a tumor vaccine actually which is a novel concept of an AML. So, vaccines as you know, are better at prevention than treatment. So, this is a maintenance drug for people in second remission or beyond who are unable to proceed to stem cell transplantation.  

So, they get the opportunity to enroll in this Phase III which is a randomized study of either GPS versus a physician’s choice which includes a wide variety of agents to choose from making it a pretty reasonable control arm and follows patients to see if the primary end point being overall survival. So, I think again for patients who achieve second remission or beyond ideally, they should proceed to stem cell transplantation. But there are several barriers to that including advanced age, comorbidities, socioeconomic barriers. So not everyone can proceed. So, for patients in that situation, there is no standardized maintenance therapy.   

And in that context I feel like an immunotherapy agent basically this vaccine which has shown very promising results in single-arm Phase I, Phase II studies is now being investigated in a Phase III study. And because it’s a trials in progress I cannot share any results with you because we don’t have any results. But I feel like people should know about this because it is open at 20 to 30 centers in the US.  

And it’s an option out there for patients who would like to participate in such a clinical trial. 

How Could Emerging CLL Treatments Impact Your Care?

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How Could Emerging CLL Treatments Impact Your Care? from Patient Empowerment Network on Vimeo.

In the changing world of chronic lymphocytic leukemia (CLL) research, how can emerging treatments impact care for patients? Dr. Jennifer Woyach shares information about targeted therapies, immunotherapy and clinical trials, and explains why she is hopeful about the future of CLL care.

Dr. Jennifer Woyach is a hematologist-oncologist specializing in chronic lymphocytic leukemia (CLL) at Ohio State’s Comprehensive Cancer Center – James Cancer Hospital & Solove Research Institute. Find out more about this expert here. 

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Transcript:

Katherine:                  

That’s a good point. Are there emerging treatments patients should know about?

Dr. Woyach:               

Yeah. There are a lot of really exciting things going on in CLL right now. And CLL is a disease that has been completely transformed in the last five to 10 years and is poised to do so again. So, I mentioned these therapies that we use for frontline treatment, and there are clinical trials now combining them together. So, these agents work so well on their own. Are they going to be even better if we add them together?

There are also newer target therapies, different targets that we are finding increasingly important in CLL, as well as a modality called CAR-T cells, which most people have heard of where we take patients’ own T cells, modify them in the lab and then, give them back with a goal of getting those cells engineered to kill CLL cells.

These are all things that are not ready for prime time in CLL yet but are available in clinical trials. And I think one other thing I’d really like to put a plug in for is clinical trials in CLL, because right now we’re at a point where our therapies are really very good. But if people just do those treatments, we are never going to figure out which one is the best or figure out, for specific types of patients, which treatment is the best. And so, I advocate that any of my patients that are eligible for clinical trials should consider them, because that’s how we make progress in the disease from an altruistic sense.

That’s how we make things better for everybody. That’s one way a patient can think about it. But more personally than that, being in a clinical trial gives somebody the opportunity to get a treatment that they otherwise wouldn’t get that might be better than our standard of care therapies.

Katherine:                  

Dr. Woyach, as a researcher in the field, why are you hopeful?

Dr. Woyach:               

I am so hopeful in CLL because there is so much that we’re learning every day about the biology of the disease, about specific mutations and other genetic factors that are important and really can be targeted by new drugs. Paralleling our understanding of the disease, there also are many more techniques to make these targeted therapies that kill cancer cells selectively while sparing normal cells and making our drugs even more tolerable.

And I think both the targeted therapies like this and the potential of combining them, figuring out sequences that are best but then, also these newer modalities where we, actually, get the immune system involved like the CAR-T cells. They’re making CAR NK cells now. And just lots of other strategies that could be used together with targeted therapies to, hopefully, cure the disease.