Why CAR-T cell therapy is the cancer killer the world needs now

Austin Wolcott was 18 years old and pretty sure he wouldn’t survive the year.

It was the summer of 2020, and Wolcott had been given the disheartening news that his Stage 4 Classical Hodgkin’s Lymphoma, which he’d been battling for just under a year, was back.

Despite aggressive chemotherapy, which briefly sent his cancer into remission, the malignancy spread to his vertebrae.

But his doctors at the Bone Marrow Transplant Clinic in Chapel Hill, North Carolina, had an idea.

Would Wolcott be willing to try a relatively new and experimental treatment, something called CAR-T therapy?

“I didn’t feel especially hopeful about it, but I was willing to try anything that may help,” says Wolcott.

Everything about CAR-T “sounded like something out of a science-fiction movie,” he says. “It was portrayed as this cancer-seeking missile that knew exactly where to go and what to do.”

That description isn’t hyperbolic, says Dr. Michael Chu, an oncologist who’s been leading CAR-T clinical trials at the Cross Cancer Institute in Edmonton, Alberta.

CAR-T therapy basically boils down to building cells that outsmart cancer, beating it at its own game.

9

“Cancers aren’t supposed to develop in humans,” Chu explains. “Our T-cells are capable of recognizing and killing mutated cells before that happens.” But cancer can be especially sneaky. “They hide their identifying barcodes so T-cells can’t see them.”

With CAR-T therapy, a patient’s own T-cells—white blood cells that fight viruses—are removed from their body and genetically edited with “a new barcode reader, hence the name chimeric antigen receptor (CAR),” Chu says.

9

Those new and improved, cancer-killing (and cancer-identifying) machines are returned to the body, ready to start an all-out cellular war.

Imagine your T-cells as mini-Terminators but without Arnold Schwarzenegger’s accent.

Although he was doubtful, Wolcott took a chance with the trial.

9

He received his first CAR-T infusion on Nov. 6, 2020. “The only side effects were some minor body aches,” he says.

Within days, his cancer was retreating.

A month later, it was gone. “As of today, I am two years, eight months, and 26 days into remission,” he says.

CAR-T therapy may not be a household name just yet, but it’s on the cusp of revolutionizing cancer treatment.

Since it was first approved by the FDA for advanced leukemia in 2017—then-FDA Commissioner Scott Gottlieb called it “a new frontier in medical innovation”—the science has jumped by leaps and bounds.

There are now six CAR-T therapies available for various blood cancers, used to target everything from lymphomas to leukemia to myeloma. 

While still in the clinical trial stages, a 2022 report from the University of Philadelphia found that two out of three patients treated with CAR-T therapy for chronic lymphocytic leukemia were, more than a decade later, still in remission.

“So many patients have been miraculously cured by CAR-T,” says Dr. John F. DiPersio, chief of the division of oncology at Washington University in St. Louis.

He’s even watched a medical colleague, a cancer surgeon, come close to death because of lymphoma and then have a complete recovery thanks to CAR-T.

The science around CAR-T has come a long way since the ‘90s, when immunologists like Dr. Michel Sadelain at the Memorial Sloan Kettering Cancer Center were first trying to convince their peers that genetically engineered T-cells were a technology worth exploring. 

9

“In the beginning, it was, ‘Why would one bother to engineer T cells?’; later it was, ‘This will not work,’” says Sadelain, who was in mice in 2003, it was, ‘This will not work in humans.’”

His ideas “ran contrary to the most common approach to stimulate T-cells, which is based in vaccines,” says Sadelain.

But with enough persistence (and some remarkable early trial results), the skepticism turned to excitement.

But also frustration.

9

While the therapy worked miracles on some patients, on many others it did nothing, for reasons that still aren’t clear.

“Tumors evolve ways to suppress the immune system,” says Dr. Brian Brown, Director of the Icahn Genomics Institute at Mount Sinai in New York City. “For example, cancers will flip a switch on T-cells to turn them off. They put a brake on the T-cells.”

How they do this, and how T-cells can outsmart cancer cells at their own game, is still being investigated.

There’s also the problem of cytokines, the pesky molecules released by CAR-T cells that promote inflammation and can lead to dangerously high fevers, vomiting, and organ failure.

9

But recent research from Dr. Michael Mitchell, an associate professor in the School of Engineering and Applied Science at the University of Pennsylvania, has developed a new method to “essentially stop cytokine release (during CAR-T therapy),” he says.

Cells are treated with sugars and injected with a polymer called polyethylene glycol, which creates what Mitchell calls a “suit of armor” around the T-cells, preventing a cytokine release.

Mitchell feels hopeful that the new technology won’t just make a difference in current CAR-T therapies, but might even demonstrate “potential to address some of the grand challenges we face using CAR-T cells to treat solid tumors.”

Solid tumors, which comprise the majority of cancers—like breast, colon, or lung cancer — have so far eluded CAR-T therapy.

9

“Blood cancers are easier to attack with CAR T-cells,” says Chu. “They’re essentially there in the blood where the CAR T-cells are first introduced. But CAR T-cells have to ‘find’ solid tumors by crossing from the blood into organs and soft tissues.”

Manipulating T-cells into super CAR T-cells — the “armored” cells that Mitchell is developing—might be the key to finally making CAR-T a feasible option for attacking solid cancers.

And then there’s the issue of cost.

The out-of-pocket infusion price can range from $375,000 to $475,000 per person.

And while many insurance providers pay at least some of the bill — Medicare, for instance, reimburses around 65% of the treatment cost — that’s just for the procedure itself.

Side effects like high fever, severe nausea, and trouble breathing can keep a CAR-T patient in intensive care for weeks, and some have walked away $1 million in debt.

“The cost must come down,” says DiPersio.

The most obvious way to do that is by reducing regulatory mandates by the FDA — which DiPersio thinks is unlikely to happen — or developing “off-the-shelf” therapies, which use engineered cells from a third party rather than a patient’s own T-cells.

Big pharma companies like Novartis are already conducting trials on off-the-shelf technology.

Another development that could affect the staggering costs is transforming the treatment from a lengthy (and costly) hospital visit into an outpatient procedure, says Brown.

“The goal is a scenario where a patient can come in, be injected with DNA or RNA that will turn a fraction of the patient’s T cells into CAR-T cells, and they will go and kill the cancer cells. That would have a big impact on cost.”

Despite all the hurdles, many of those involved in CAR-T cell research are cautiously optimistic about where the technology is heading.

“This is the tip of the iceberg,” says Chu. “There are CAR T-cells that have shown significant activity against glioblastoma multiforme — the most common brain cancer, including the one that killed Senator John McCain—and some forms of muscle and bone cancers.”

Brown says CAR-T therapy has the potential to be used beyond just cancer, like inflammation, and autoimmune disease, “and possibly even to treat aging,” he says. “It’s not science fiction because all of these things have already been demonstrated in animal models and will eventually move to humans.”

Though these seismic shifts won’t happen overnight—“outside of pandemics, medicine moves slowly,” Brown says — it’s still remarkable what they’ve achieved so far.

What made Brown believe that this therapy was something special — that “we’re living just a few minutes after the Big Bang,” as he puts it —are the statistics.

9

“It’s very common for us to read results from clinical trials of new drugs and you have to squint to see the difference,” he says. “You read how the drug extended the life of sick patients from a six-month survival to an eight-month survival.” 

But with CAR-T, he says, the numbers are more startling. “They’re reporting remissions of more than a year, and you don’t have to be a radiologist to see the differences. The tumor masses hadn’t just shrunk, they were completely gone from these patients.”

For Wolcott, who’s now 22 and living with his wife—whom he met soon after he got sick — in Greensboro, NC, he’s still in shock that the cancer he thought would kill him remains (for the moment) in his rear-view mirror.

“The day I found out I was officially in remission felt like the first day of my life,” he says.

9

To salute 1,000 days of being cancer-free, Wolcott celebrated with a trip in September to the Blue Ridge Rock Festival.

Standing and dancing for hours in the blazing Southern sun would’ve been unthinkable for Wolcott just a few years ago.

“There was a time during my treatment where I felt like I’d spend the rest of my life locked inside,” Wolcott says. “Every day that I’m alive and out in the world again, I feel grateful.”