Wikipedia Deep Dive

CAR T cell

14 min read

In 2012, a six-year-old girl named Emily Whitehead was dying. She had acute lymphoblastic leukemia, a cancer of the blood that had resisted two rounds of chemotherapy and come roaring back twice. Her doctors had run out of options. They offered her parents an experimental treatment that had never been tried on a child before—one that would reprogram her own immune cells to hunt down and destroy her cancer.

Emily became the first pediatric patient to receive what we now call CAR T cell therapy. She nearly died from the treatment itself when her immune system went into overdrive. But she survived. And her cancer vanished.

More than a decade later, Emily remains cancer-free.

Teaching Cells to Kill

Your immune system is already pretty good at killing things. T cells—a type of white blood cell named for the thymus gland where they mature—patrol your body constantly, looking for cells that don't belong. When they find a virus-infected cell or a foreign invader, they destroy it.

But cancer is tricky. Cancer cells are your own cells gone wrong. They've learned to hide from the immune system, to disguise themselves as normal tissue, to suppress the very cells that might destroy them. T cells often can't recognize cancer as a threat.

What if you could teach them to see it?

That's the fundamental insight behind chimeric antigen receptors, or CARs. The word "chimeric" comes from the Chimera of Greek mythology—a creature made of parts from different animals, typically depicted with a lion's head, a goat's body, and a serpent's tail. A chimeric antigen receptor is similarly stitched together from pieces of different proteins, combining abilities that no natural receptor possesses.

Think of it like this: T cells recognize threats using special receptors on their surface, but these natural receptors are picky about what they'll respond to. A CAR takes the targeting system from an antibody—a different type of immune protein that can be designed to recognize almost anything—and fuses it to the activation machinery of a T cell. The result is a T cell that can be programmed to attack any target you choose.

Building a Living Drug

The manufacturing process for CAR T cells sounds like science fiction, but it's now happening in specialized facilities around the world.

First, doctors draw blood from the patient—typically through a process called leukapheresis, where blood is circulated through a machine that separates out the white blood cells and returns everything else. From this collection, technicians isolate the T cells specifically.

Then comes the genetic engineering. Scientists use a modified virus—typically derived from HIV, ironically—as a delivery vehicle. These viral vectors have been gutted of everything dangerous and repurposed as microscopic syringes that inject new genetic instructions into the T cells. The instructions tell the cells to build chimeric antigen receptors and display them on their surface.

The modified cells are then grown in bioreactors, multiplying from millions to billions over the course of about two weeks. Quality control checks ensure the cells are healthy and properly engineered.

Meanwhile, the patient undergoes what's euphemistically called "lymphodepletion"—chemotherapy designed to temporarily suppress their existing immune system. This clears space for the new CAR T cells and triggers the release of signaling molecules called cytokines that help the engineered cells expand once infused.

Finally, the cells are infused back into the patient's bloodstream. Unlike conventional drugs that get metabolized and eliminated, these engineered cells are alive. They circulate through the body, hunting for their target. When they find it, they multiply. A single CAR T cell can spawn thousands of copies of itself, all carrying the same cancer-targeting instructions.

This is what researchers mean when they call CAR T cells a "living drug."

The Target Matters

The first successful CAR T therapies targeted a protein called CD19. This wasn't a random choice—it was a strategic one.

CD19 sits on the surface of B cells, a type of immune cell involved in producing antibodies. It's present on essentially all B cell cancers, including certain leukemias and lymphomas. But here's what makes it such a good target: CD19 is also found on normal, healthy B cells.

Wait—doesn't that mean CAR T cells would attack healthy tissue?

Yes. And that's actually okay.

Humans can survive without B cells. It's not ideal—you become more susceptible to certain infections and need regular infusions of antibodies—but it's manageable. This "on-target, off-tumor" effect is an acceptable trade-off when the alternative is death from cancer.

The same logic doesn't work for most solid tumors. If you engineered CAR T cells to attack a protein found on lung cancer cells, you'd likely find that protein on healthy lung tissue too. Unlike losing your B cells, losing your lungs isn't compatible with life.

This is why CAR T therapy has been so successful against blood cancers but struggled with solid tumors. The ideal target antigen would be something expressed on every cancer cell but absent from every healthy cell. Such antigens are rare, and even when they exist, solid tumors present additional challenges: dense tissue that's hard for T cells to penetrate, and a local environment that actively suppresses immune responses.

When the Cure Almost Kills

Emily Whitehead nearly died not from her cancer, but from her treatment.

After her CAR T cell infusion, her temperature spiked. Her blood pressure crashed. Her lungs filled with fluid. She slipped into a coma and was put on a ventilator. Her doctors feared they'd killed her.

What Emily experienced was cytokine release syndrome, or CRS—the most common and dangerous side effect of CAR T cell therapy. When engineered T cells find their target and start killing cancer cells en masse, they release enormous quantities of inflammatory signaling molecules called cytokines. These molecules recruit more immune cells, amplifying the response. The result can resemble the body's response to severe infection: fever, dangerously low blood pressure, difficulty breathing, organ failure.

The cruel irony is that CRS is actually a sign that the treatment is working. The worse the initial reaction, generally, the more cancer cells are being destroyed. Patients with larger tumor burdens tend to have more severe CRS because there's more for the CAR T cells to kill.

Emily's doctors discovered that a rheumatoid arthritis drug called tocilizumab could interrupt the inflammatory cascade. Tocilizumab blocks interleukin-6, one of the key cytokines driving the syndrome. Within hours of receiving it, Emily began to improve. She woke from her coma on her seventh birthday.

Tocilizumab has since become standard supportive care for CAR T cell therapy, used either to treat severe CRS or given preemptively to prevent it. Research suggests that early intervention doesn't compromise the therapy's effectiveness—the CAR T cells continue killing cancer even as the inflammatory response is dampened.

Minds Under Siege

Beyond cytokine release syndrome lies another troubling side effect: neurotoxicity.

Some patients experience confusion. Others develop difficulty speaking—they can understand language perfectly well but can't produce coherent words, a condition called expressive aphasia. Some become drowsy or unresponsive. A few have seizures. In rare cases, the brain swells dangerously.

In early clinical trials, several patients died from cerebral edema—swelling of the brain severe enough to be fatal. A trial run by Juno Therapeutics lost five patients this way. Another trial reported an irreversible neurological death more than four months after treatment.

The mechanism remains poorly understood. It may be related to cytokine release syndrome, or it may be a separate phenomenon entirely. CAR T cells can cross the blood-brain barrier, and they may trigger inflammation in the central nervous system. Some researchers suspect that certain target antigens—or proteins similar to them—might be expressed in brain tissue.

What's particularly unsettling is the unpredictability. Some patients sail through treatment with mild fatigue and a low fever. Others require intensive care. Doctors still can't reliably predict who will have severe reactions.

Generations of Design

Not all CAR T cells are created equal. The field has evolved through what researchers call "generations" of design, each more sophisticated than the last.

First-generation CARs, developed in the late 1980s and early 1990s, were relatively simple. They combined an antibody-like targeting domain with the signaling portion of a protein called CD3-zeta—the part of the natural T cell receptor that actually triggers activation. These early designs could get T cells to recognize and attack target cells, but they didn't work very well in patients. The engineered cells didn't persist in the body, and tumors rarely shrank.

Second-generation CARs added a co-stimulatory domain—an extra signaling component that T cells normally need to become fully activated. Think of it like the difference between turning on a car's ignition versus turning on the ignition and stepping on the gas. The most common co-stimulatory domains are CD28 and 4-1BB, borrowed from proteins that provide these "second signals" in natural immune responses. All currently approved CAR T products use second-generation designs.

Third-generation CARs incorporate two co-stimulatory domains, theoretically providing even stronger activation. Fourth-generation CARs, sometimes called "armored" CARs, add additional features: some produce cytokines to enhance their own activity, while others express proteins that help them resist the immunosuppressive environment inside tumors.

Each generation represents an attempt to make the living drug more powerful, more persistent, or safer. The engineering possibilities are vast, and researchers continue to explore new architectures.

Beyond Cancer

The original vision for CAR T cells focused entirely on cancer, but the technology has broader implications. Any disease involving a cell type you'd like to eliminate becomes a potential target.

Consider autoimmune diseases, where the immune system mistakenly attacks the body's own tissues. What if you could design CAR T cells to eliminate the rogue immune cells causing the damage? Early studies are exploring this approach in conditions like lupus—formally known as systemic lupus erythematosus—where B cells produce antibodies against the patient's own DNA. Some of the same CD19-targeting CAR T cells used against leukemia might be able to eliminate these self-attacking B cells.

There's also an intriguing twist on the concept: rather than engineering killer T cells, what about engineering regulatory T cells—a subset of T cells whose job is to calm down immune responses? A CAR-equipped regulatory T cell could potentially suppress immune reactions against specific targets. This could help prevent rejection of transplanted organs or quiet the inflammation in diseases like rheumatoid arthritis.

Clinical trials are underway for CAR T cells in systemic sclerosis—a condition where the immune system attacks connective tissue throughout the body—and in various forms of arthritis. The results remain preliminary, but the concept is sound: the same precision-targeting capability that makes CAR T cells effective against cancer might work against other diseases of immune dysfunction.

The Problem of Solid Tumors

Blood cancers were the low-hanging fruit. The cancer cells circulate freely, making them accessible to CAR T cells throughout the bloodstream. Good target antigens exist. Patients can tolerate the loss of healthy B cells.

Solid tumors are different in almost every way.

First, there's the access problem. A tumor mass is a dense, disorganized structure, often surrounded by a fibrous shell and supplied by abnormal blood vessels. CAR T cells struggle to penetrate from the periphery to the center. Even when they do reach the tumor, they may be outnumbered by the sheer mass of cancer cells.

Then there's the microenvironment problem. Solid tumors don't just sit passively in the body—they actively reshape their surroundings to suppress immune responses. They recruit regulatory cells that quiet attacking T cells. They deplete nutrients that T cells need. They produce signaling molecules that exhaust immune cells and render them ineffective. A CAR T cell that arrives in peak fighting condition can be worn down to uselessness by the hostile local environment.

Finally, there's the target problem. Most proteins found on solid tumor cells are also found on healthy tissue somewhere in the body. The few tumor-specific antigens that exist are often expressed inconsistently—some cancer cells display them, others don't. Target only the cells expressing the antigen, and you leave behind cancer cells that can regrow.

Researchers are attacking these problems from multiple angles. Some are engineering CAR T cells to produce their own support signals, counteracting the suppressive microenvironment. Others are developing CARs that recognize multiple antigens simultaneously, reducing the chance that cancer cells can evolve resistance. Still others are exploring ways to deliver CAR T cells directly into tumors rather than infusing them into the bloodstream.

Progress has been made—CAR T cells have shown effectiveness against glioblastoma, one of the deadliest brain cancers—but solid tumors remain the frontier.

A Turning Point in Medicine

The first CAR T cell therapies received FDA approval in 2017. Tisagenlecleucel—sold under the brand name Kymriah—was approved for a type of childhood leukemia. Axicabtagene ciloleucel—branded as Yescarta—followed for a form of lymphoma. As of today, six CAR T products have received FDA approval, with many more in clinical trials.

The numbers tell a remarkable story. In trials of patients with relapsed or refractory B-cell cancers—people whose disease had returned after treatment or never responded to it—CAR T therapy produced complete remissions in a substantial fraction. These were patients who had exhausted conventional options. Some of them, like Emily Whitehead, have now been cancer-free for more than a decade.

But the technology remains limited in important ways. Manufacturing is complex and expensive—a single CAR T cell treatment can cost several hundred thousand dollars. The process takes weeks, during which patients' cancers may progress. The cells don't work for everyone, and even when they do work, relapses occur.

Researchers are working on "off-the-shelf" allogeneic CAR T cells—products manufactured from healthy donor cells that could be used for any patient, eliminating the wait time and potentially reducing costs. But introducing foreign cells raises its own complications, particularly the risk that the donor cells will attack the patient's healthy tissues.

We're also in the early days of understanding long-term effects. What happens to patients decades after receiving engineered cells? Do CAR T cells persist indefinitely, providing ongoing protection? Can they themselves become cancerous, transformed by the very genetic engineering that created them? The viral vectors used to deliver CAR genes insert their cargo somewhat randomly into the genome—what if they disrupt a tumor suppressor gene or activate an oncogene?

These concerns aren't purely theoretical. Scientists have developed techniques to analyze where in the genome CAR genes land, looking for patterns that might predict problems. So far, the evidence suggests that transformation is rare. But rare events become visible only with large numbers of patients followed over long periods.

The Road Ahead

What began in 1987 with a paper describing antibody fragments fused to T cell receptor components has become a new pillar of cancer medicine. The early researchers—Yoshihisa Kuwana's team in Japan, Gideon Gross and Zelig Eshhar in Israel, Arthur Weiss at the University of California, San Francisco—couldn't have known that their basic science would lead to treatments capable of curing previously incurable cancers.

The first clinical trials, in the 1990s, were failures. First-generation CARs targeting HIV-infected cells produced no improvement. Early attempts at solid tumors went nowhere. It would take another two decades of incremental advances—better CAR designs, better manufacturing processes, better supportive care—before the technology delivered on its promise.

As of recent counts, more than 350 clinical trials involving CAR T cells were ongoing worldwide. Most still target blood cancers, with CD19 and BCMA—a protein expressed in multiple myeloma—as the leading antigens. But the field is expanding rapidly: new targets, new diseases, new engineering strategies.

The fundamental insight remains as powerful as ever. T cells are exquisitely efficient killers. Give them the right target, and they will find it and destroy it. The challenge is in the details—which target, which design, which patients—and in ensuring that the treatment doesn't cause more harm than the disease.

Emily Whitehead graduated from high school in 2024. She wants to study science. The cells that saved her life are still circulating in her blood, ready to attack any cancer that might return.

They haven't had to yet.