CAR T Cells: Engineering Immune Cells to Treat Cancer
Research on CAR T-cell therapy is progressing rapidly to improve the cancer treatment, expand its use to more cancers, and better manage its side effects.
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For decades, the foundations of cancer treatment have been surgery, chemotherapy, and radiation therapy. These continue to be critical mainstays of treatment, but new categories of treatment have recently helped transform the treatment picture for people with cancer.

The 2000s marked the emergence of targeted therapies like imatinib (Gleevec) and trastuzumab (Herceptin)—drugs that find and kill cancer cells by homing in on specific molecular changes seen primarily in those cells. Dozens of targeted therapies are now standard treatments for many cancers.

And over the past decade, immunotherapy—therapies that enlist and strengthen the power of a patient's immune system to attack tumors—has rapidly become what many call the "fifth pillar" of cancer treatment. That’s because immune system–boosting drugs have shown the ability to shrink, and even eradicate, tumors in some people with advanced cancer. In a small percentage of patients, these treatment responses can last for years.

Drugs called immune checkpoint inhibitors, for instance, are already in broad use to treat people with many types of cancer, including melanoma, lung, kidney, bladder, and lymphoma.

But another form of immunotherapy, called CAR T-cell therapy, has also generated substantial excitement among researchers and oncologists. Although CAR T-cell therapies are not as widely used as immune checkpoint inhibitors, they have shown the same ability to eradicate very advanced leukemias and lymphomas and to keep the cancer at bay for many years.

Since 2017, six CAR T-cell therapies have been approved by the Food and Drug Administration (FDA). All are approved for the treatment of blood cancers, including lymphomas, some forms of leukemia, and, most recently, multiple myeloma.

Despite the excitement around these therapies, they lead to long-term survival in fewer than half of the patients treated. They have also come under criticism for their cost, which, in the case of the most recently approved CAR T-cell therapy, is more than $450,000.

Nevertheless, after years of painstaking research, CAR T-cell therapies have entered the mainstream of cancer treatment, said Steven Rosenberg, M.D., Ph.D., chief of the Surgery Branch in NCI's Center for Cancer Research (CCR), an immunotherapy and CAR T-cell therapy pioneer.

"[CAR T cells] are now widely available in the United States and other countries and have become a standard treatment for patients with aggressive lymphomas,” Dr. Rosenberg said. “They have become a part of modern medicine.”

CAR T-cell therapy: A "living drug"

CAR T cells are the equivalent of "giving patients a living drug," explained Renier J. Brentjens, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center in New York, another early leader in the CAR T-cell field.

As their name implies, T cells—which help orchestrate the immune response and directly kill cells infected by pathogens—are the backbone of CAR T-cell therapy.

Currently available CAR T-cell therapies are customized for each individual patient. They are made by collecting T cells from the patient and re-engineering them in the laboratory to produce proteins on their surface called chimeric antigen receptors, or CARs. The CARs recognize and bind to specific proteins, or antigens, on the surface of cancer cells.

These receptors are "synthetic molecules, they don't exist naturally," explained Carl June, M.D., of the University of Pennsylvania Abramson Cancer Center, another leader in the cellular therapy field.

After the revamped T cells are “expanded” into the millions in the laboratory, they’re then infused back into the patient. If all goes as planned, the CAR T cells will continue to multiply in the patient's body and, with guidance from their engineered receptor, recognize and kill any cancer cells that harbor the target antigen on their surfaces.

The CAR T-cell therapies approved by FDA to date target one of two antigens on B cells, CD19 or BCMA.

New treatment options where few existed

The initial development of CAR T-cell therapies focused largely on the most common cancer in children, acute lymphoblastic leukemia (ALL).

More than 80% of children diagnosed with ALL that arises in B cells, the predominant type of pediatric ALL, will be cured by intensive chemotherapy. But effective treatments have been limited for patients whose cancers return, or relapse, after chemotherapy or a stem-cell transplant.

In 2017, however, a new option appeared, with FDA’s approval of tisagenlecleucel (Kymriah), the first CAR T-cell therapy to be approved by the agency, based on clinical trials demonstrating it could eradicate cancer in children with relapsed ALL.

In some cases, CAR T-cell therapy has now been studied long enough that details about the long-term outcomes in children are beginning to emerge.

An NCI-led research team, for example, recently reported on long-term follow-up from children with relapsed ALL who had been treated with CAR T cells as part of a clinical trial. More than half the children went on to receive a potentially curative stem-cell transplant, they found, and approximately 60% of those children were still alive 5 years later without their cancer coming back or the children experiencing any disease-related problems.

The progress made with CAR T-cell therapy in children with ALL "has been fantastic," said Terry Fry, M.D., who has led several clinical trials of CAR-T cell therapies at NCI and, more recently, at Children's Hospital Colorado. As CAR T-cell therapy has become more widely available, Dr. Fry said, it has rapidly become the standard of care for children with relapsed ALL.

CD19-targeted CAR T cells are also offering hope to adults and children with advanced aggressive lymphomas. Before the development of CAR T cells, many of these patients “were virtually untreatable," said James Kochenderfer, M.D., of NCI’s Center for Cancer Research, who has led several trials of CAR T-cell therapies in patients with diffuse large B-cell lymphoma.

The results in lymphoma to date "have been incredibly successful," Dr. Kochenderfer said, "and CAR T cells [have] become a frequently used therapy for several types of lymphoma."

Understanding and managing the side effects of CAR T-cell therapies

Like all cancer treatments, CAR T-cell therapies can cause severe side effects, including a mass die-off of antibody-producing B cells and infections. One of the most frequent and serious side effects is cytokine release syndrome (CRS).

As part of their immune-related duties, T cells release cytokines, chemical messengers that help stimulate and direct the immune response. In the case of CRS, the infused T cells flood the bloodstream with cytokines, causing serious side effects, including dangerously high fevers and precipitous drops in blood pressure. In some cases, severe CRS can be fatal.

Ironically, CRS is considered an "on-target" effect of CAR T-cell therapy—that is, its presence demonstrates that T cells are at work in the body. Generally, patients with the most extensive amount of cancer in their bodies are more likely to experience severe CRS from CAR T cells, Dr. Kochenderfer explained.

In many patients, both children and adults, mild forms of CRS can be managed with standard supportive therapies, including steroids. And as researchers have gained more experience with CAR T-cell therapy, they've discovered ways to better manage the more serious cases of CRS.

A big part of that management is the drug tocilizumab (Actemra). This drug, initially used to treat inflammatory conditions like juvenile arthritis, blocks the activity of IL-6, a cytokine that is often secreted in large amounts by T cells and macrophages.

The other side effect of particular concern with CAR T-cell therapies is neurologic effects, including severe confusion, seizure-like activity, and impaired speech. The precise cause of these neurologic side effects (also called immune effector cell–associated neurotoxicity syndrome, or ICANS) is still unclear.

Although it’s effective for treating CRS, tocilizumab doesn’t seem to help with ICANS. Steroids are currently the best treatment option for severe ICANS, particularly dexamethasone, which is better at penetrating the central nervous system than other steroids, explained Jennifer Brudno, M.D., who is involved in several trials of CAR T-cell therapies in NCI’s Center for Cancer Research.

Different ways of preventing CRS and ICANS are now under intense study, Dr. Brudno said. One approach is the prophylactic use of tocilizumab and low-dose steroids. Although further studies are needed, “the data so far are reassuring,” she said.

Other treatments for ICANS are being investigated. Smaller studies, for example, have found that anakinra (Kineret), which is used to treat rheumatoid arthritis, may help prevent severe ICANS in patients treated with CAR T-cell therapies.

One more idea for protecting against severe CRS and ICANS is to modify the CARs themselves, Dr. Brudno explained.

In a small clinical trial of adults with lymphoma, for example, patients treated with a “remodeled” CD-19-targeted CAR T cell developed at NCI had far fewer severe neurologic side effects than historically seen with the original form of the same CAR.

More target antigens, including for solid tumors

Research on CAR T cells is continuing at a swift pace, including hundreds of ongoing clinical trials. Part of this expansion is a product of researchers having identified additional antigens on tumor cells that might be good targets for CAR T cells.

Although CD19 and BCMA are the only antigens for which there are FDA-approved CAR T-cell therapies, CAR T-cell therapies have been developed that target other antigens commonly found in blood cancers, including therapies that target multiple antigens at one time.

But what about the use of CAR T cells to treat solid tumors, like brain, breast, or kidney cancer? There, advances have been hard to come by. Efforts to identify antigens that are on the surface of solid tumors but not healthy cells, Dr. Rosenberg said, “have largely been unsuccessful.”

Another obstacle with solid tumors is their surrounding environment. Physical barriers, for example, can prevent the infused CAR T cells from reaching tumor cells. Other components of the microenvironment, such as immune-suppressing molecules produced by tumor cells or other immune cells, can cause CAR T cells to malfunction, leaving them unable to carry out their cell-killing duties.

Perhaps the biggest barrier is “an age-old problem: tumor heterogeneity,” said Crystal Mackall, M.D., director of the Parker Institute for Cancer Immunotherapy at Stanford University.

In other words, solid tumors of the same cancer type can be molecularly quite different from patient to patient, and even within a particular patient. For example, there may be no targetable antigens on some tumor cells, or maybe there are, but not enough of them for CAR T cells to function as they’re supposed to.

Despite these obstacles, researchers continue to try to find ways to use CAR T cells to treat solid tumors.

One approach involves trying to outwit the immune-suppressing environment of many advanced solid tumors. Several research groups, for example, have developed what are known as “armored” CAR T cells that can navigate through this difficult microenvironment by secreting specific cytokines and other molecules.

Other researchers are pursuing more conventional approaches, relying on standard CAR-engineering technologies and targeting a single surface antigen on cancer cells.

After promising results from laboratory and animal-based studies, for instance, Dr. Mackall’s group at Stanford launched an NCI-supported clinical trial of CAR T-cell therapies that target a protein on solid tumors called B7-H3. In another trial, her group is investigating a CAR T-cell therapy that targets a molecule on cancer cells called GD2 in some children and young adults with a uniformly fatal brain cancer called DIPG.

For the GD2 CAR T-cell trial, how it was initially envisioned and how it has been carried out are quite different, Dr. Mackall explained at the 2021 annual meeting of the Society for Immunotherapy of Cancer.

Initially, patients were going to be treated only with an initial intravenous infusion of CAR T cells. But results from animal model studies of a similar CAR T-cell therapy led the researchers to alter the trial: patients who respond to the initial intravenous infusion were given additional smaller doses infused directly into the brain.

The ability to give patients multiple doses, she reported, has led to improvements in tumor responses (e.g., reductions in tumor size) and their cancer-related symptoms.

The research team was also able to rapidly make modifications to the GD2 CAR T cells used in the trial and how they’re manufactured, both to improve their potential efficacy and safety. The ability to make such swift changes highlights the critical importance of continued innovation with cellular therapies, Dr. Mackall said.

“I think all of us in this field know that we’re just scratching the tip of the iceberg about what we can do with regard to engineering these CAR T cells,” she said. “There are many, many next-generation approaches to the problems that are limiting [their effectiveness] in solid tumors.”

Off-the-shelf CAR T-cell therapies: CRISPR, natural killers, and mRNA

Researchers have also begun to rethink the source of immune cells for CAR T-cell therapies—using T cells collected not from patients, but from healthy donors. The goal: “off-the-shelf” CAR T-cell therapies that would be immediately available for use rather than having to be manufactured for each patient.

All of the FDA-approved CAR T-cell therapies rely on a disarmed virus to deliver the genetic material into T cells to produce the CAR. But for the off-the-shelf CAR T cells now being tested in small clinical trials, gene-editing technologies like TALON and CRISPR are being used to induce the donated T cells to produce CARs.

Other off-the-shelf CARs also use a different type of immune cell, called natural killer (NK) cells. Much of this research is still in its early days, but some CAR NK cell therapies are already being tested in small clinical trials.

And not only is the source of T cells and the type of immune cell being reconsidered, but so is where the therapies are actually made. Several research groups, for instance, are using nanotechnology and mRNA-based approaches that allow CAR T cells to be created inside the body.

Not just a last-ditch cancer treatment?

For the most part, CAR T-cell therapy isn’t a consideration until a person’s cancer has already gotten worse after multiple other treatments. But that’s beginning to change.

Recently, in two large clinical trials, CAR T-cell therapy proved to be more effective than the standard treatment for patients with non-Hodgkin lymphoma whose cancer returned after their initial, or first-line, chemotherapy.

The finding led some experts to conclude that, for these patients, CAR T-cell therapy could soon replace more chemotherapy as the standard second-line treatment.

For some kids with ALL, Dr. Fry said, using CAR T cells in this way would be particularly attractive. Specifically, he pointed to kids who are at high risk of their disease returning after their initial chemotherapy, which typically is given for about 2.5 years. Small clinical trials are already underway, in fact, of CAR T cells in children with ALL who aren’t having an optimal response to their initial chemotherapy treatment.

For patients who respond well, "they could be spared 2 more years of chemotherapy," Dr. Fry said. "That's amazing to think about."