Using Armored CAR T-Cells to Tackle Solid Tumors

Renier Brentjens, MD, PhD
Credit: Roswell Park

One of the ongoing challenges in oncology cell therapy is applying chimeric antigen receptor T-cell (CAR-T) therapy, which has proven efficacious in blood cancers, to solid tumors. One of the methods currently being explored for this purpose is armored CAR T-cells.

In an interview with Renier Brentjens, MD, PhD, the chair of the department of medicine and the deputy director at Roswell Park Comprehensive Cancer Center, CGTLive® asked Brentjens about the current state of CAR-T therapy in oncology. Brentjens explained the rationale behind developing armored CAR T-cells for solid tumors and how these next-generation products are shifting how oncologists and investigators see the role of CAR-T in addressing cancers.

CGTLive: Can you introduce yourself?

Renier Brentjens, MD, PhD: I am currently the chair of medicine and the deputy director at Roswell Park Comprehensive Cancer Center. I came to Roswell Park now 3 and a half years ago from Memorial Sloan Kettering Cancer Center in New York City, where over 20+ years there we developed some of the first promising data with CAR T-cells. We ran some of the first CD19-targeted CAR T-cells anywhere as a clinical trial and were the first to publish the efficacy of CD19-targeted CAR T-cells in adult patients with relapsed and refractory acute lymphoblastic leukemia. Subsequent to that, that technology was licensed out to a company, Juno, which was then bought by Celgene, and that was then bought by Bristol Myers Squibb, and some of the work that we did there with Dr. Eric Smith is currently in phase 2 trials for multiple myeloma targeting GPRC5D.

Can you discuss the current state of CAR-T in oncology?

I think that, although there's still work to be done in blood cancers with CAR T-cell treatments, whether it's treating high-risk patients earlier on in the disease course or whether it's redesigning the construct or the targets that you want to go after—it is very clear that while there's still room for improvement—the concept of engineered T-cells to recognize target antigens in blood cancers is reasonably well-established. Again, I strongly suspect that 5 to 10 years from now, FDA-approved CAR T-cells will look a lot different than they do today. One of the platforms that we developed while I was still in New York City was this concept of an "armored CAR T-cell". I guess since we came up with the name we get to we get to come up with the definition as well: an armored CAR T-cell is a CAR T-cell that's been engineered with a CAR, but can be additionally engineered with any kind of payload. What we initially looked at are proinflammatory cytokines, although you could add ligands or single-fragment-length antibodies. There's a bunch of different types of armoring that can be done. These in the preclinical setting, and now starting to be seen in the clinical setting, can enhance CAR T-cell function.

An armored CAR is designed to address not just the target and the viability of the CAR T-cell itself and the cytotoxicity of a CAR T-cell, but because the payload can be anything—for example, a proinflammatory cytokine—it can also modulate that tumor microenvironment where the tumor resides, which in turn can then potentially further elicit a patient's own endogenous, nongenetically-manipulated immune system to help target and kill off the tumor.

While this is certainly relevant in the context of blood cancers, it's even moreso relevant in the context of solid tumors, which are a lot more common than blood cancers and also are a lot more immunologically complex. Solid tumor cells tend to scaffold themselves with stromal cells and other immune cells that are designed to hide them from the patient's immune system. As such, they tend to be very immune suppressive. To a degree, when you talk about this approach in solid tumors, you can make all the tumor-targeted CAR T-cells that you want, but if those T-cells encounter this suppressive immune system they can be just basically canceled out. So I think for us, at least when we were working on leukemias and lymphomas, this wasn't as much of an issue. But very early on, when we were working on moving over that chasm between blood cancers and solid tumors, we became aware that the formula, as it were, that we use now for blood cancers doesn't really apply or probably won't really meaningfully give clinical benefit to patients with solid tumors. Then an additional issue that was even seen with blood cancers, but even moreso in solid tumors, is that the targets that you go after are not universally expressed by all the tumor cells. What we call antigen escape can happen more commonly than we would like in blood cancers, but is much, much more likely from the get-go to happen in solid tumor cancers.

That's all the more the reason that you want to design a CAR T-cell, in this case an armored CAR T-cell, that will elicit the endogenous immune system to help go after tumors that may not express the antigen that is targeted by the CAR T-cell. Where we are now, and where I would envision the future is for solid tumors, is that we still have a lot of engineering to do. That engineering means that we get the CAR T-cell to the site of the tumor, which is step 1, but once it's there, we have to make sure that it persists, it survives, and it modulates that tumor microenvironment.

It's interesting because when you look at a solid tumor, more than half the cells are not actually tumor cells. They are stromal cells like fibroblasts and they are immune cells like tumor-associated macrophages and regulatory T-cells, all of which conspire to to inhibit the the immune system. What we've described in the past are cytokines such as IL12 and IL18, which actually can kind of tip the balance from immune suppression to a proinflammatory one. What we found as a consequence of that is that at least in our initial mouse models, where we look at this, is that these these further-engineered armored CAR T-cells not only enhance the survival of the CAR T-cell and the function of the CAR T-cell itself at the tumor site, but also change the balance from suppressive to proinflammatory, which we believe is ultimately the way that these CAR T-cells will be able to eradicate tumors.

I think in its first iteration, when we first started designing these, we saw CAR T-cells as being just cytotoxic agents going around killing anything that expresses the target antigen that it's designed to go after. I think over the brief 20 year span that I've been doing this work, I think we philosophically kind of changed how we look at that and we realize that the CAR T-cell may be more of a spark rather than the actual explosion. It's the spark that sets off a downstream effect where an immune system that is actually quite reasonably sophisticated in recognizing cancer cells can overcome the defenses that cancer cells create around themselves to stop cell therapies from working. As such, we actually do think that this next generation of armored CAR T-cells will probably be the format that will demonstrate efficacy in the clinical setting in solid tumors.

This transcript has been edited for clarity.