CAR T Cells - Engineering Immune Cells To Treat Cancer - NCI

9/30/23, 1:20 PM CAR T Cells: Engineering Immune Cells to Treat Cancer - NCI
CAR T Cells: Engineering Patients’ Immune Cells

to Treat Their Cancers
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
Co-stimulatory signaling domains
homing in on specific molecular changes seen
have been added to newer
primarily in those cells. Dozens of targeted
generations of CAR T cells to
therapies are now standard treatments for many improve their ability to produce
cancers. more T cells after infusion and
survive longer in the circulation.
And over the past decade, immunotherapy— Credit: Brentjens R, et al. “Driving CAR T
therapies that enlist and strengthen the power of a cells forward.” Nat Rev Clin Oncol. 2016 13,
patient's immune system to attack tumors—has 370–383.
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.
https://www.cancer.gov/about-cancer/treatment/research/car-t-cells#:~:text=Unlike CARs%2C which use portions,that are inside tumor cells. 1/10
Since 2017, six CAR T-cell therapies have been approved by Get
the Food and Drug Administration (FDA). All are approved for Answers >
the treatment of blood cancers, including lymphomas, some
Need help
forms of leukemia, and, most recently, multiple myeloma. finding cancer
treatment
Despite the excitement around these therapies, they lead to information?
long-term survival in fewer than half of the patients treated. Contact a Cancer
They have also come under criticism for their cost, which, in Information
Specialist for
the case of the most recently approved CAR T-cell therapy, is
assistance. It's
more than $450,000. free and
confidential.
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.
Making a CAR T Cell

A growing number of CAR T-cell therapies are being developed and tested in clinical
studies. Although there are important differences between each specific therapy that
can affect how they function in patients, they all share similar components. Each CAR
bridges the cell membrane. Part of the receptor is located outside the cell and part
within the cell. The part of the CAR that extends out from the cell’s surface is usually
composed of fragments, or domains, of lab-made antibodies. Which domains are used
affects how well the receptor recognizes or binds to the antigen on tumor cells. The
internal part of each CAR has signaling and "co-stimulatory" domains. These transmit
signals into the cell after the receptor interacts with an antigen. The different domains
that are used can affect the cells' overall function.
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 Second CAR
therapy to be approved by the agency, based on clinical trials T-Cell
demonstrating it could eradicate cancer in children with Therapy
Approved
relapsed ALL.
for
Lymphoma
In some cases, CAR T-cell therapy has now been studied long Tisagenlecleucel
enough that details about the long-term outcomes in is a new option
children are beginning to emerge. for some patients
with common
lymphoma.
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 Remodeled
prophylactic use of tocilizumab and low-dose steroids. CAR T-Cell
Therapy
Although further studies are needed, “the data so far are
Causes
reassuring,” she said.
Fewer Side
Other treatments for ICANS are being investigated. Smaller Effects
studies, for example, have found that anakinra (Kineret), For people with
which is used to treat rheumatoid arthritis, may help prevent lymphoma,
severe ICANS in patients treated with CAR T-cell therapies. treatment safer,
as effective as
original CAR T
One more idea for protecting against severe CRS and ICANS
cell design.
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 Overcoming
infused CAR T cells from reaching tumor cells. Other T Cell
Exhaustion
components of the microenvironment, such as immune-
in
suppressing molecules produced by tumor cells or other
Immunotherapy
immune cells, can cause CAR T cells to malfunction, leaving
them unable to carry out their cell-killing duties. Targeting
proteins involved
Perhaps the biggest barrier is “an age-old problem: tumor in T cell
heterogeneity,” said Crystal Mackall, M.D., director of the exhaustion may
boost
Parker Institute for Cancer Immunotherapy at Stanford immunotherapy.
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 CAR T-Cell
launched an NCI-supported clinical trial of CAR T-cell Study
Suggests
therapies that target a protein on solid tumors called B7-H3.
Promise for
In another trial, her group is investigating a CAR T-cell
therapy that targets a molecule on cancer cells called GD2 in Childhood

some children and young adults with a uniformly fatal brain Cancers
cancer called DIPG.
In mouse models
of common
For the GD2 CAR T-cell trial, how it was initially envisioned pediatric cancers,
and how it has been carried out are quite different, Dr. treatment shrank
Mackall explained at the 2021 annual meeting of the Society or eradicated
for Immunotherapy of Cancer. tumors.
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: NCI Aims to

CRISPR, natural killers, and mRNA Boost CAR
Researchers have also begun to rethink the source of T-Cell
immune cells for CAR T-cell therapies—using T cells collected Therapy
Clinical
not from patients, but from healthy donors. The goal: “off-
Trials
the-shelf” CAR T-cell therapies that would be immediately
available for use rather than having to be manufactured for Initiative will
each patient. manufacture
therapies to be
All of the FDA-approved CAR T-cell therapies rely on a tested at multiple
trial sites.
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 CAR T Cells:
until a person’s cancer has already gotten worse after Second-
multiple other treatments. But that’s beginning to change. Line
Treatment
Recently, in two large clinical trials, CAR T-cell therapy proved Option for
to be more effective than the standard treatment for NHL?
patients with non-Hodgkin lymphoma whose cancer
returned after their initial, or first-line, chemotherapy. Clinical trials
show CAR T cells
may be more
The finding led some experts to conclude that, for these
effective than
patients, CAR T-cell therapy could soon replace more standard
chemotherapy as the standard second-line treatment. 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."
More than Just CAR T Cells: TILs and TCRs

CAR T cells have garnered the lion's share of attention when it comes to cellular
therapies. But other types of cellular therapies have also shown promise in small clinical
trials, including in patients with solid tumors.
One type, known as tumor-infiltrating lymphocytes (TILs), uses immune cells that have
penetrated the environment in and around the tumor. Researchers at NCI were the first
to use TILs to successfully treat patients with advanced cancer—initially in

melanoma and later in several other cancers, including cervical cancer. More recently,
NCI researchers have developed a technique for identifying TILs that recognize cancer
cells with mutations specific to that cancer and identifying people whose cancers are
more likely to respond to TIL therapy.
The other type of cellular therapy involves engineering patients' T cells to express a
specific T-cell receptor (TCR). Unlike CARs, which use portions of synthetic antibodies
that can recognize specific antigens only on the surface of cells, TCRs use naturally
occurring receptors that can also recognize antigens that are inside tumor cells.
To date, TCR T cells have been tested in patients with a variety of solid tumors, showing
promise in melanoma and sarcoma.
Related Resources
T-cell Transfer Therapy
New Drugs, New Side Effects: Complications of Cancer Immunotherapy
Updated: March 10, 2022
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9/30/23, 1:20 PM CAR T Cells: Engineering Immune Cells to Treat Cancer - NCI

CAR T Cells: Engineering Patients’ Immune Cells

The 2000s marked the emergence of targeted

patient's immune system to attack tumors—has 370–383.

rapidly become what many call the "fifth pillar" of

CAR T-cell therapy: A "living drug"

Making a CAR T Cell

New treatment options where few existed

In 2017, however, a new option appeared, with FDA’s

Understanding and managing the side effects of CAR T-cell

Different ways of preventing CRS and ICANS are now under

More target antigens, including for solid tumors

Another obstacle with solid tumors is their surrounding

One approach involves trying to outwit the immune-suppressing environment of many

After promising results from laboratory and animal-based

therapy that targets a molecule on cancer cells called GD2 in Childhood

Initially, patients were going to be treated only with an initial

Off-the-shelf CAR T-cell therapies: NCI Aims to

Not just a last-ditch cancer treatment?

More than Just CAR T Cells: TILs and TCRs

to use TILs to successfully treat patients with advanced cancer—initially in

Updated: March 10, 2022

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