Dual-Acting CAR T-Cell Therapy May Address Unmet Need in the Treatment of Patients with B-Cell Malignancies

Cokey Nguyen is the chief scientific and technical officer at Atara Biotherapeutics, and he joins Pharmacy Times to discuss ATA3431, a novel dual-acting chimeric antigen receptor (CAR) that has undergone preclinical studies for the treatment of B-cell malignancies.

Nguyen discusses the glass ceiling of some of the current single antigen-targeting CAR T therapies, the necessity for scaleable and accessible therapies, the importance of CD20 expression as a target for recurrent disease, and increased efficacy and safety benefits that may be associated with this new CAR therapeutic and its development.

PT Staff: What is the mechanism of action of bispecific CAR ATA3431?

Cokey Nguyen: So ATA3431 is a dual CAR, and how this differs from the other approved CAR Ts in the space is that it has 2 chimeric antigen receptors in 1. And it's seeing 2 antigens that we know are on normal B cells, but also, more importantly, on the tumor cells in patients’ bodies. This is CD19 and CD20. And the reason why we're excited about this program is because it gives you the ability to deal with something that we see in the clinic a lot, and that's antigen escape.

With targeted therapies, your therapies are as good as your antigen and ensuring that your antigen is expressed. So, while we've seen tremendous data with CD19 targeted therapies, we felt like having this in our armamentarium, seeing CD20 and CD19 would have greater patient benefit.

And in fact, I think that's what you see in the clinic with the autologous programs. They tend to have response rates that look higher than the CD19-only programs, and the complete response (CR) rate, which is even more important, seems to be even higher.

One of the problem statements in the field is that when you have a CD19 CAR T program, there's almost like a glass ceiling. And we're really only starting to understand that, but we've kind of seen the ceiling for CR anywhere in the 60% - 70% rate, when you start to see the CR rate in large B-cell lymphoma that's more like an 80 - 90% rate (which is, what we think we're seeing with these earlier CD19/CD20 programs) I think that really opens more space more ability to treat patients earlier so that they can be exposed to fewer lines of treatment before they see these CAR T programs.

PT Staff: If this treatment were eventually approved, when (in the series of treatments administered for b-cell malignancies) could this treatment be administered?

Cokey Nguyen: You know, there's a lot of open space right now. So let me let me first just say that CD20 is a really well-validated antigen. That's the target of rituximab (Rituxan; Genentech, Biogen) and frontline therapy, which is what's called R-CHOP, which is rituximab plus chemotherapy. And this is the standard treatment for patients in the space across a lot of hematologic disorders. So that's another reason why we felt like CD19 and CD20 were the right choice— we don't think that CD19/CD20 expression is lost after treatment with R-CHOP. What we understand is that patients can have stable disease after R-CHOP, but then they'll relapse but still maintain that CD20 expression. So with a program where you can target CD20 and CD19, you can now— like we were talking about earlier—get into the space for disease interception almost.

PT Staff: Unlike previous generations of off-the-shelf CD19-targeted CAR T-cell products, this product will target CD19 and CD20. What is the significance of having these 2 drug targets?

Cokey Nguyen: That's a great question, and obviously 1 I think the field is grappling with. Early reports from the field from the CD19, and this started earlier with Glenna, which is the CD3 engager which targets CD19. Physicians treating patients had started to see was you would see this initial benefit for the patients. And then over time, the patients would relapse for reasons we don't fully understand. But in some cases, what happens is you lose CD19 expression (and it's pretty clear in the pre- and post- treatment). So that was 1 cautionary note that, “Hey, you know, if we're able to target 2 antigens, we may able to create a more durable response for the patients.”

And so let me give you an example of a target antigen in comparison with CD20. A lot of other approaches might try to target CD22— an earlier approach with a dual CAR-hitting CD19 and CD22, it really didn't show clinical benefit. That had to do with not only 2 things: it's the antigen expression of CD22, but also the CAR design, that dual-targeting design. It couldn’t bind to both antigens. So there's 2 things that really we're talking about here.

The number 1 is the target antigen was validated and expressed at high levels. So CD20 hits that. Check. It's actually expressed at very high levels on tumor cells, and a lot of other antigens such as CD22 are not. And then the second question is, “Can you efficiently target it with a validated binder?” And that's a design space issue. Where can you create something that can maintain your ability to target CD19 and also hit CD20? So there's a lot of design that goes into that.

So if you walk through the 3 levels: 1) Is CD20 a great antigen? Yes. it's the mechanism of rituximab frontline therapy; 2) Do you see CD20 on the relevant tumor antigen of the population patients? Yes, absolutely. It seems to be maintained throughout disease (early stage versus late stage) even after 6 lines of therapy and then 3) Can you make a therapeutic to target both antigens? And I think so, yes.

Image credit: David A Litman | stock.adobe.com

PT Staff: In preclinical studies, what toxicities were associated with ATA3431?

Cokey Nguyen: So this is one of the key things for CAR Ts— we know that oftentimes there is a lot of toxicity associated with these drugs. The toxicities can come from the lymph depletion regimen, as well as the drugs themselves. You see this in large B cell, and you also see this in myeloma. So when we study this preclinically, this again goes back to the concept of CD20 as an antigen. It's a very safe antigen. It isn't expressed anywhere except on B cells. And in fact, it's the restriction of CD20 that is actually more restricted than CD19. So CD19 tends to be on developmentally-free B cells and B cells and immature B cells, whereas C 20 is really just mature B cells.

So when we do our preclinical studies, we're looking at primary cells from healthy donors, as well as patients-derived samples to see if there are any off-target effects, and so we've looked and we haven't seen anything, and this really recapitulates what you see with rituximab, [which is] that it's a very safe drug.

PT Staff: Whatare current barriers to care/knowledge gaps for this disease, and how does this CAR T-cell therapy address them?

Cokey Nguyen: There's many levels to your question. And I think the first is what was “What is the standard of care?” And “What happens when patients their disease relapses? What are their options?” Now, what we see is that autologous CAR T is a great answer. We, in the field, didn't know if it was a commercially viable proposition because it's really expensive— hundreds of 1000s of dollars. And your patients basically go into the intensive care unit (ICU), which is also very expensive for the patients. And it's also very restrictive (there are only certain medical centers in the US [that administer CAR T] and you have to live within 50 miles of them).

So it's a couple things. “Can you make the drug at scale for 1000 patients?” It's very challenging from that aspect. [And] that's the second part. “Can you make the drug? Can you get it to patients?” And I think the third aspect is really, “Does the drug give you the right benefit for how much it costs and also potential off-target effects? Do you get durable responses at 6 months to 1 year?” [Looking] at it through this lens, 1) what is the unmet need? 2) What is the current state of CAR T? And 3) Do the patients benefit?

I think a lot of CAR T companies in the field are asking, “Can we do better?” And I think the answer is yes. From those 3 parameters, there is still unmet need, that's the first thing. And I think the second thing is, and you're probably aware because you're in the space and I see that you write a lot of great articles about it, we have capacity constraints with autologous CAR T. It’s very difficult, the logistics of this, to have 24/7 manufacturing when a patient gets their T cells to the facility to get created and made into CAR Ts, and then you get it back to the patient. It's really difficult to do that even on the 100s, but when you scale into the 1000s that's a big ask, whether or not we as an industry can really do that in a viable way for economics.

And I think the last piece is one we don't always talk about, and that is patient benefit. Let's say [CAR T is like] running a cross country race. You have the sickest kids in your school and you're asking them to run the cross-country race, and that's unfair to them. That's what CAR T is— you're taking really sick patients who have pretty beat up immune systems and you're saying, “Hey, why don't you run this 10-mile race?”

Now, you could go 1 click further and say “Well, let's try from the healthier kids. Let's just randomly select 20 healthy kids.” [But] most cross-country teams have a tryout— you're just trying to get the 5 to 10 best runners to score and win the meet. So that's how we look at it. It's this process where you can't just pick randomly 20 kids from your school to run the race and hope they all do well. What you're trying to do is have a tryout, you're trying to choose the best runners to compete for your school in that cross country meet, and we're trying to do the same thing with AlloCAR T right?

Looking at the issue, we’re saying that part of the reason why you're not seeing the benefit for patients is we're creating immune cells from very sick people. These are really not fit T cells. So if you have the opportunity to have an off-the-shelf platform to choose the best T cells, and then you had time to really vet that and validate that and then infuse those healthy T cells, we think that the better process of making T cells (but also more fit T cells) is going to have patient benefits that [are] higher.

PT Staff: What is the role of the pharmacist as part of the care team in this possible new treatment paradigm?

Cokey Nguyen: I think that pharmacists are key to the way we treat patients in the US. You can look at other examples where pharmacists have this key decision-making ability, so they mak[e] this key decision about “What is the best and safest drug that I'm going to stock because I can't stock everything.”

Now, when you take that in cell therapy, it's analogous in the sense of, “Do I want to have this infusion process where I have to put this patient on bridging therapy for 2 to 3 weeks while this drug is being made? Hopefully it is successfully made [and] comes back and can be infused in this patient.”

That's also really difficult because what you're asking a patient to do is to say, “I've failed 4 to 6 prior lines of therapy. My cancer is progressing super rapidly and you want me to go back on chemotherapy, which is really unhealthy for me as a patient, for 3 weeks?”

Hopefully, that holds the disease back so that [the patient] can be infused with this autologous product. However we think there's a better model and we've kind of shown that with tabelecleucel (tab-cel; Atara), which is our first generation Epstein Barr virus (EBV) T cell product.

The tab-cel model is that the patients go on R-CHOP (rituximab/chemotherapy) first, [but] a significant population then relapse pretty aggressively. But if you can get them tab-cel within the 3 to 5 days, you get this amazing overall survival of 1 to 2 years— more than 90% of patients survive, where otherwise they would succumb within 30 to 40 days.

We want to take that same model and bring it to the pharmacist at the point of care and say, “Same idea. This patient has failed 2 lines of therapy [and] their disease is progressing rapidly. We think that we have a disease that has cost of goods which are more like antibodies because you can mass produce them, but also, we think it's a better drug because it's made from healthy donor T cells and you can treat the patient within the week.”

We want to make it easy for the patients to come to any center, not just major medical centers, and we want the physicians and pharmacists to have it right there ready for them to treat the patients.