CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers

A "living drug"

As their name indicates, T cells are the backbone of CAR T-cell therapy. And because it uses T cells collected from the patient, with this form of treatment "we are giving patients a living drug," explained Renier J. Brentjens, M.D., Ph.D., of Roswell Park Comprehensive Cancer Center in Buffalo, NY, another early leader in the CAR T-cell field.

Making these treatments begins with collecting blood from the patient and separating out the T cells. These cells are then sent to one of the treatment manufacturer's laboratories, where they are genetically engineered to produce special proteins on their surfaces called chimeric antigen receptors, or CARs.

The CARs help the cells to latch on to specific proteins, known as antigens, that are present on cancer cells (and some normal cells). They also enhance the T cells' ability to kill cancer cells.

Next, these revamped T cells are grown, or "expanded," until there are hundreds of millions of them. These expanded cells are the final CAR T-cell therapy product, which is sent back to the hospital to be returned to the patient as a single infusion. 

Currently, this entire process—from the initial blood collection to the cells being infused back into the patient—takes about 3 weeks.

After the infusion, if all goes as planned, the T cells will continue to expand in the patient's body and, with guidance from their special receptors, kill any cancer cells that have the target antigen on their surfaces. 

CAR T-cell therapies for adults and children

More than 80% of children diagnosed with ALL that arises in B cells are cured by intensive chemotherapy. But for many years there were no effective treatments for children whose cancers returned, or relapsed, after chemotherapy or a stem cell transplant.

Managing the side effects of CAR T-cell therapies

Like all cancer treatments, CAR T-cell therapies can cause severe side effects. Among the most common for these immunotherapies are infections and a mass die-off of antibody-producing B cells

Two other side effects of particular concern are cytokine release syndrome (CRS) and neurologic problems collectively called immune effector cell–associated neurotoxicity syndrome (ICANS), explained NCI’s Jennifer Brudno, M.D., who studies CAR T-cell therapies for blood cancers.

In the case of CRS, the infused T cells flood the bloodstream with cytokines, which are chemical messengers that help stimulate and direct the immune response. The overabundance of cytokines that happens with CRS, however, causes dangerously high fevers and precipitous drops in blood pressure. In rare cases, severe CRS can be fatal.

In many patients, both children and adults, CRS can be managed with tocilizumab (Actemra) and, if needed, steroids, Dr. Brudno said. Tocilizumab, which was 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 immune cells.

Some of the hallmark signs of ICANS include confusion, excessive sleepiness, and impaired speech. ICANS is also often treated with steroids, Dr. Brudno explained. 

When steroids aren’t working to control ICANS, several studies have found that anakinra (Kineret), an antibody drug used to treat rheumatoid arthritis, may be an effective option. Other studies have suggested that giving anakinra shortly after CAR T-cell therapy may help to prevent ICANS or reduce its severity.

Closing in on CAR T-cell therapy for solid tumors

In contrast to the advances in CAR T-cell therapies for blood cancers, progress in developing them for solid tumors has lagged. 

Part of the problem is that researchers have struggled to identify antigens that are present on the surface of cancer cells in solid tumors but not on healthy cells and are also good candidates to target with a CAR, Dr. Rosenberg said. 

Another major obstacle is the so-called immunosuppressive environment in and around tumors. For example, tumor cells and other components of the immune system produce molecules that can cause CAR T cells to malfunction or prevent them from reaching the tumor.

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

Solid tumors of the same cancer type can be molecularly quite different from patient to patient, and even within a patient. For example, there may be no targetable antigens on some tumor cells, or not enough of them for CAR T cells to function as intended.

But the tide may be about to turn for solid tumors.

Dr. Mackall’s group at Stanford, for example, has reported promising results from a small clinical trial of a CAR T-cell therapy in some children and young adults with a fatal brain cancer called diffuse midline glioma. Another research team has also reported encouraging findings using a different CAR T-cell therapy in children with these cancers. 

Positive results have also been seen in small clinical trials testing CAR T-cell therapies in people with other solid cancers, including ovarian and colorectal cancers.

“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,” Dr. Mackall said. “There are many, many next-generation approaches to the problems that are limiting [their effectiveness] in solid tumors.”

What comes next?

Research on refining CAR T-cell therapies is moving at a brisk pace.

For example, researchers have developed CAR T-cell therapies designed to have fewer side effects, that could be used for any type of blood cancer, and that have multiple distinct CARs. Some of these newer forms of CAR T-cell therapies are already being studied in small clinical trials.

In addition, large clinical trials are testing CAR T-cell therapies that use T cells collected from healthy donors instead of individual patients. By using donated, or allogeneic, T cells, these CAR T-cell therapies can be made in advance and, like other cancer drugs, be available immediately as “off-the-shelf” treatments for any patient rather than manufactured over a period of weeks for individual patients.

Because these CAR T cell therapies use donated T cells, however, they require additional genetic engineering to prevent patients’ immune systems from recognizing the T cells as foreign and attacking them.

Researchers are also investigating using CAR T-cell therapies earlier in treatment, instead of reserving them until multiple other treatments have stopped working. The approved uses of two CAR T-cell therapies have already been expanded so that they can be used as so-called second-line treatments—that is, after the initial, or first-line, treatment has stopped working—for adults with some blood cancers.

This approach is also being studied in children. One clinical trial, for example, is testing a CAR T-cell therapy as a second-line treatment in children with what is called “high-risk” B-cell ALL for whom the standard initial chemotherapy hasn’t fully eliminated their cancer after 6 months. 

These children typically receive chemotherapy for 2.5 years, said Terry Fry, M.D., who has led CAR T-cell therapy trials at Children’s Hospital Colorado. In this trial, instead of continuing with chemotherapy that doesn’t appear to be working as well as hoped, children are switched to CAR T-cell therapy.

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