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Given all the understandable pessimism there is about the world, you might not realize that we’re living in a golden era of cancer treatment.
In January, the American Cancer Society reported that the five-year survival rate of cancer in the U.S. is now 70%—the highest mark reached to date. Preventive screening programs and the decline in major risk factors like smoking have played a big role in that success, to be sure, but doctors today are also able to treat and manage cancers that were once considered a death sentence.
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One of the more groundbreaking advances in cancer treatment has been chimeric antigen receptor T cell therapy, simply known as CAR T cell therapy. This therapy uses T cells, usually taken from the patient’s body, that have been genetically reprogrammed to express receptors that correspond to a specific target antigen. They can then “see” and attack cancer cells carrying that antigen.
CAR T was first approved in the U.S. in 2017, and various forms of it nowadays are used for several blood cancers that have failed to respond to earlier interventions. A sizeable percentage of people with these difficult-to-treat cancers respond well to CAR T, though some types are less responsive than others, while many people with otherwise fatal cancers can experience a sustained remission or even a full cure.
“The ceiling is just so much higher on what you can do with a living drug than what you could do with any of these other drugs.”
There are many scientists whose work helped make CAR T cell therapy a reality. One of these early pioneers is Renier Brentjens, currently the deputy director and chair of the Department of Medicine at the Roswell Park Comprehensive Cancer Center in Buffalo.
Among other things, Brentjens helped conduct the early research that showed CAR T could be used to target blood cancers carrying the CD-19 antigen; he and his colleagues at Memorial Sloan Kettering actually also coined the term CAR T. In 2024, he was one of four scientists given an award by the Warren Alpert Foundation for their pivotal role in the therapy’s fruition. And even today, he’s working to develop the next generation of CAR T cells that can hopefully target a wider variety of cancers, particularly solid tumors.
I recently had the chance to speak with Brentjens about the current state of CAR T cell therapy, the large hurdles it has yet to overcome, and what its future might look like. The following conversation has been edited for grammar and clarity.
**Ed Cara, Gizmodo:** Why has CAR T emerged as a breakthrough therapy for at least some cancers? What differentiates it from the standard chemotherapies and the other interventions out there?
**Renier Brentjens:** One of the most defining things about it is that it’s a living drug. So you design immune cells to recognize cancer cells, which are done outside the patient’s body, and then you infuse the now CAR T cells back into the patient. These cells that would otherwise have ignored the tumor now can recognize and kill it. But there’s a lot of drugs that can do that. The difference here is that the immune cells can perpetuate, they can persist.
And because it’s a cell, you can also reprogram it to do a lot more things than a simple drug could be used for. An antibody does one thing, one thing only—it recognizes a target and then can carry a payload, etc. But immune cells, by virtue of the fact that they’re living, the ceiling is much higher for what they can do.
**Gizmodo:** What are some of the challenges facing CAR T today?
**Brentjens:** So for starters, there are economic and timing issues. It’s very expensive. The way it’s currently designed, you have to take your own cells out. It takes a couple weeks for the company or academic center to make the cells, and then you infuse them back in. So it takes time, and currently those that are FDA approved are very expensive. Those are the pragmatic issues.
The clinical issue is that when you infuse a large population of immune cells that recognize a target, they become activated, and so there are side effects that are related to that. And these side effects—we never saw them in our mice, but they became very quickly apparent in patients when we started treating them. Which is always the reason why clinical research needs to be done with a high degree of expertise and supervision.
Then there are immunological limitations. And one of the obvious immunological limitations is that you’re making a cell that recognizes only one protein. There are versions of these CAR T cells that can recognize two, but that doesn’t really take care of the one big issue that we have, which is that a cancer cell is not necessarily beholden to expressing the target that you’re going after. And that means a process called antigen escape can happen. So even if one of the millions of cancer cells stops expressing the target, that cell now has a selective advantage, and then that tumor can grow out, regardless of whether you have CAR T cells there or not. Because those CAR T cells can’t recognize the target antigen-negative tumor now.
“The long-term legacy of CAR T cells will depend on if you can cross over to solid tumors.”
What is also biologically important, which is something we didn’t realize 30 years ago when we started working on this, is that tumors are immunologically very complex. And we need to somewhat separate out blood cancers and solid tumors here. The blood cancers are where the success has been, specifically in B cell cancers and in multiple myelomas. Those are cancers that are much lower-hanging fruit to use this technology with.
But solid tumors, much more common tumors like colon cancer, breast cancer, etc., are much more immunologically complex. And what I mean is that a solid tumor is actually more like a potpourri of cells. Only about half of the cells inside there are actual cancer cells. The other half of the cells, they’re things like fibroblasts that give it structure and may protect it from the immune system. And then there are a whole bunch of immune cells that are not pro-inflammatory, but they’re immune-suppressive. And as much as I spent decades looking at those cells as the bad guys, the fact of the matter is that the immune system is a very complicated system of checks and balances.
So if you have an immune response to something, there have to be other immune cells that put the brakes on that response so you don’t melt down every time you get a viral infection. And so what the tumor cells do is they co-opt those brakes, and they introduce them into the tumor, and then they coat it with a coating of fibroblasts, so you can imagine that the immune system has a difficult time getting in.
Furthermore, the targets that may be expressed on a solid tumor may not be ubiquitously expressed, which is to say that some of the tumor cells may express what you design your CAR T cells to recognize, but others don’t.
These are all additional issues that need to be addressed to enable us to actually get similar outcomes in solid tumors that we currently have in B cell cancers.
**Gizmodo:** What are some of the ways you’re trying to overcome these limitations in your current work?
**Brentjens:** When we initially started doing this work 30 years ago, we said, “Let’s design an immune cell that recognizes a cancer cell and kills it.” And that’s probably where we were at the time as far as complexity goes.
What we know now is that we need to take advantage of all the things that a CAR T cell could provide. A CAR T cell can find a tumor through its receptor, and then it can proliferate there, so it can expand there, which is great. But that also allows us to introduce into the tumor other things that can change the biology of the solid tumor. So one of the things that we’ve been working on for some time now is this idea of an “armored” CAR T cell—the CAR T name lends itself to a lot of car analogies, obviously.
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The idea here is that not only do you introduce a receptor that allows it to recognize and kill the tumor cells, but you can then add a whole bunch of luggage to the trunk of that car. And that luggage can be anything. We’ve used cytokines, which are proteins that stimulate the immune system. And so if you can get a CAR T cell to go into that hostile and immune-suppressive solid tumor, and once it gets there, it introduces a sort of kryptonite, a cytokine that stimulates not just the CAR T cells but a whole bunch of other parts of the immune system to now start killing the tumor, then you can get a lot more bang for your buck.
Now there are a lot of issues associated with that, because as I alluded to earlier, one of the clinical issues of CAR T is that if the immune system starts reacting to the tumor, you get fevers, and that’s also mediated by cytokines. And these cytokines can cause cytokine release syndrome. And we already see that happen with unarmored CAR T cells. So you can imagine that you have to be extremely cautious with these newer CAR T cells because you’re fanning the flames when you introduce a cell that secretes its own pro-inflammatory cytokines. So there are still a lot of unanswered questions as of now.
**Gizmodo:** There are other novel forms of CAR T being studied right now, such as creating “off-the-shelf” CAR T cells from donors or trying to edit a person’s T cells from inside the body directly rather than taking the cells out first (in vivo CAR T). What do you make of these different approaches?
**Brentjens:** So it’s clear that these other approaches could potentially save you a lot of time and probably a lot of cost. And I think all of these are very commendable approaches, but they’re also remarkably complex.
The idea of doing off-the-shelf CAR T has been around for a significant amount of time, and a significant number of clinical trials have been done. But at least as of now, none were found to be superior, and in fact, many are found to be inferior to using your patient’s own T cells. I think that to date, the best way of testing CAR T cells is still with a patient’s own T cells, taken out, engineered in the lab, and then reinfused. It doesn’t mean that’s the only way, but if you’re going to get this to work in as many cancers as possible, that’s probably the platform you should initially use.
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I think it’s very commendable that there are other folks that are trying to make it more accessible to more patients, less costly, etc. But every one of those approaches that I’m aware of, at least those that have been proposed to date, have a pretty long list of limitations that we have not yet overcome. And if you compound the limitations of getting it to work in a solid tumor and compound that with the limitations of doing it off the shelf or in vivo, then you’re almost setting yourself up to fail.
The philosophical, or just pragmatic, way I look at it is that we should first get things to work with autologous CAR T, the most expensive way possible, and then use that as the standard. And from there, we can then see if you can replicate that success with these cheaper or easier methods.
**Gizmodo:** To close things out, where do you see both the near- and long-term future of CAR T cell therapy going?
**Brentjens:** In the near term, I think there have to be better CAR T cell constructs.
Right now, the FDA-approved CAR T therapies are based on the design of a receptor that we published in 2002 and another group published in 2003. That’s what’s currently FDA approved. That was at the start of this technology. And it’s been 20-plus years since.
You could stack all the journal articles that we have on next-generation CAR T cells, and it would be three feet high. So if you would have told me 20 years ago that our work would still be the go-to, I mean, it’s like having a horse and carriage, right? It’s outdated. So near-term, you would hope that some of these next-generation constructs and designs would be utilized. And you would hope that the survival and the cure rate get even higher for the blood cancers that are currently FDA approved for.
I also think that near-term improvements in production may bring the price down and that accessibility hopefully goes up as it becomes more common and more people are around that can give these drugs.
The other thing is that right now the efficacy of this therapy has been illustrated as a third-line or fourth-line treatment. But these therapies are going to be the best as frontline treatments. If you can identify people that you know are unlikely to respond to chemotherapy, give them the CAR T cells early.
The T cells will be healthier because people won’t be exposed to as much chemotherapy by the time they need it. And there are those that will say, “Well, yeah, but it’s so much more expensive.” But I argue that if you create a drug that, with a single infusion, can cure you of your disease, then economically, the long-term cost benefit is that you don’t spend weeks in the hospital with neutropenic fever, and you don’t spend weeks getting cycle after cycle after cycle of chemotherapy.
I mean a single infusion of a living drug that can get you into remission is far more favorable than six cycles of chemotherapy before finding out that the disease did come back. So moving CAR T closer to the front line, I think, will have a significant impact.
The long-term legacy of CAR T cells will depend on if you can cross over to solid tumors. But I assure you that the design currently FDA approved for blood cancers is going to look a lot different for solid tumors. That blueprint is not going to work. I’m confident that we’ll be able to eradicate solid tumors—there’s a lot of mice that can attest to that. It’s just going to take a lot more ingenuity and innovation. But that’s also the great thing about working with a product like an immune cell. The ceiling is just so much higher on what you can do with a living drug than what you could do with any of these other drugs. So to a degree, it’s a lot more fun working with this technology because you get to be a lot more creative.
