Ask a cancer researcher what the breakthrough treatment of the decade is, and they’ll tell you CAR T takes the crown.
The therapy genetically engineers a person’s own immune cells, turning them into super soldiers that hunt down cancerous blood cells. With astonishing speed, multiple CAR T therapies have been approved by the FDA for previously untreatable blood cancers. So far, over 15,000 patients have been treated with the therapy.
To Dr. Carl June, a pioneer of the technology at the University of Pennsylvania, we’re only scratching the surface of CAR T’s potential.
In a perspective article published in Nature this week, June and colleagues laid out a path forward.
At its root, CAR T therapy taps into the natural “killer instinct” of a type of immune cell, called a T cell, and directs it to a particular target—for example, blood cancer cells. But with careful redesign, CAR T therapy can be genetically engineered to tackle a wide range of humanity’s most prominent medical enemies: autoimmune diseases, asthma, and heart, liver, and kidney diseases caused by increasingly stiffening muscles.
Even more intriguing, CAR T may help clean out senescent “zombie” cells, which are linked to age-related diseases, or combat HIV and other viral infectious diseases.
“We are only beginning to realize the full potential of this living drug,” said the authors.
What’s CAR T Again?
CAR T stands for “chimeric antigen receptor T therapy.” I like to think of it as a Mr. Potato Head with plug-and-play parts.
The core “potato” is the immune T cell, a family of cells that normally survey our bodies to seek out and destroy invaders such as cancer or infections. Add to this CAR “parts”: genetically engineered protein “hooks” that can grab onto a specific protein on a diseased cell.
CAR T was first developed to battle HIV—with lackluster results—but it rose to prominence for its efficacy at treating blood cancers. Here’s how it usually goes: a patient’s T cells are isolated from a blood draw and genetically enhanced with CAR protein constructs in the lab. After being infused back into the body, the super-soldiers evade tumor cells’ defenses, with a single engineered cell killing hundreds if not thousands of cancerous enemies.
CAR T is truly “a new pillar of therapy,” said the authors. With T cells involved in other diseases, can the therapy do more?
A Solid Struggle
The first move to expand CAR T beyond blood cancers is targeting solid cancers—think pancreatic, breast, colon, and others. Sadly the results have “largely been disappointing” in multiple clinical trials so far, said the authors.
But from these failures, we’ve learned tons. Unlike blood cancers, solid tumors build a local biological “fortress” and pump out chemicals that hold T cells at bay and dampen their destructive activity. One idea to help them break through is directly injecting CAR T cells into tumors. Another is to use CRISPR to equip CAR T cells with a genetic profile—adding or deleting certain genes—that evades these defenses.
Unfortunately, other barriers remain. Solid tumors are often composed of an amalgam of cells, each with its distinct fingerprint of surface proteins. This makes it difficult for a single CAR T design to hunt down all cancerous cells. Some protein targets, called antigens, also dot the outside of healthy cells, causing collateral damage.
Then there’s the chance of stirring an immune hurricane. Here, CAR T cells rapidly expand inside the body to battle their cancerous target, but in turn drive the body’s immune system into crisis mode—a condition called “cytokine release syndrome.” The end result can be devastating, with fever, a rapid drop in blood pressure, and even multi-organ failure.
As with any other medication, dosage is key. One potential way to avoid immune overdrive is to give T cells a time-limited boost. Instead of adding CAR directly into a cell’s genetic code that permanently transforms them into CAR T super soldiers, a workaround is using mRNA—the “translator” of genes. The end result is similar, with the cell suited up for action with its new CAR proteins. But unlike genetic inserts, mRNA is temporary, meaning that CAR T cells can shed their super soldier personas and return to their usual T cell identity—in turn allowing the immune system to calm down.
An Expanding Universe
Solid cancers are hard to crack, but the good news is their defenses don’t exist for other diseases. For example, autoimmune disorders, diabetes, heart muscle stiffening, or zombie cells generally don’t have a protective fortress, meaning it’s easier for CAR T to tunnel in and retain their killer activity. Unlike cancers—notorious for their ability to mutate—these diseases often have a steady genetic profile, so that CARs can retain their efficacy.
So far, the most promising use of CAR T outside of cancer is for autoimmune diseases.
Back in 2022, a small clinical trial in patients with systemic lupus erythematosus (SLE)—a life-threatening autoimmune disorder—found that CAR T cells rapidly expanded in their bodies and relieved symptoms.
SLE is the most common type of lupus. Here, the body’s immune system wages war on its own tissues. The main culprit is another type of immune cell, called a B cell, which normally produces antibodies to fight off infections. In autoimmune diseases, B cells mistake friend for foe, tagging healthy tissues—heart, lung, kidneys—as targets for elimination.
After CAR T therapy, none of the five people in the trial relied on their daily immunosuppressive drugs any longer. Surprisingly, their B cells returned a few months later, but without any symptoms or damage to their organs.
In another proof of concept, a team used CAR T for a patient with anti-synthetase syndrome, an autoimmune disease that wrecks the lungs and muscles and causes arthritis. Three months later, the patient’s muscles improved, along with less inflammation in the lungs.
Scientists are now experimenting with CAR T in mouse models of severe asthma, with the cells protecting against severe attacks that last long after the treatment itself. Other efforts are tackling autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, which affect the protective sheath around nerves.
Although promising, current CAR T configurations don’t discriminate between healthy or diseased B cells. Multiple efforts are optimizing CAR “hooks” to specifically target harmful ones. One study in mice for hemophilia—a bleeding disorder—found that the newer designs left healthy B cells alone. Clinical trials for testing the design are underway.
The Wild West
Here’s where CAR T gets truly experimental.
Take cardiac fibrosis—the stiffening of heart muscles—which can happen after injury or chronic disease or during aging, and eventually leads to heart failure. There are few treatment options.
In a proof of concept, a study last year found that directly reprogramming T cells inside the bodies of mice using mRNA reversed scar tissue in their hearts after a single injection. Fibrosis doesn’t only happen to hearts. Liver, kidneys, lungs, and muscles also suffer from similar stiffening, making them ideal targets for CAR T therapy.
“With a dearth of therapies targeting fibrosis directly, CAR T cells may provide a potent and selective way of treating such diseases,” said the authors.
But perhaps the most daring use of CAR T therapy is destroying senescent “zombie” cells. Although alive, these cells don’t fulfill their normal duties, instead pumping out a cadre of toxic molecules into their surroundings. Tons of evidence shows that removing these cells with chemicals or genetic engineering increases healthspan, but with varying efficacy.
Here’s where CAR T can help. Senescent cells have specific antigens, making them perfect targets for the therapy. One study that treated mice with lung cancer and liver disease found that removing zombie cells prolonged life.
Conclusion? CAR T cells are rapidly expanding beyond oncology. Roadblocks remain: the therapy is highly expensive and potentially dangerous for triggering immune storms. We don’t yet know if the cells can damage—or rejuvenate—healthy tissues as they navigate the body.
But to the authors, we’re entering the next chapter of a transformative treatment. “The theoretical applications are vast, and the platform is powerful…we are only beginning to realize the full potential of this living drug.”