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number to be much lower, says immunologist Bruce Levine of
the Perelman School of Medicine, University of Pennsylvania,
who collaborates with the company. For this treatment, in
addition to adding the CAR, researchers activate the cells with a
costimulatory antibody. Then they grow the engineered cells in
bioreactors before returning them to the patients.
Unfortunately, receiving CAR T-cell therapy is no Sunday drive.
One of the signs it’s working is that the patient gets miserably,
dangerously sick. Amping up the immune system causes the cells
to release signaling molecules called “cytokines,” and can lead to
a “cytokine storm.” This causes symptoms such as nausea, fatigue, and fever—a handful of patients have died as a result.
But when it works, it works wonders. During an early trial in
2010, Levine and his colleagues calculated that each of their
three patients lost between 2.5 and 8 pounds of leukemia cells.
Two of those patients are alive today.
Seeking the “Holy Grail”
Despite these successes, CAR T-cell therapy remains immature. “We have a Model A Ford,” says Brentjens. “We need
a Ferrari.” Reducing toxicity is a key goal. One backup system
researchers are exploring is to include a self-destruct gene in
their CAR T cells, such as a caspase cell suicide gene, that can
be turned on by a medication, so they can delete the engineered
cells if necessary.
Another major challenge is to take CAR T-cell therapy beyond
blood cancers. Even though the treatment attacks all of the cells
expressing CD19—cancerous and healthy ones—patients can live
for a time without those kinds of cells. That’s not the case with
the body’s organs.
“The ‘Holy Grail’ would be a molecule expressed on all tumor
cells that is not expressed on any healthy cell in the body,” says
John Maher, an immunologist and clinician at King’s College
CAR aficionados have limited choices for targets because the
CARs can only access molecules on the surface of cancer cells.
That’s why some scientists prefer to work with natural TCRs,
which recognize snippets of internal proteins displayed on a cell’s
surface. “In a way, the TCRs dig inside the cancer cells,” says
Chiara Bonini of San Raffaele University and Hospital in Milan,
Italy. She is working on a procedure to take a patient’s T cells,
A team led by Steven Rosenberg at the National Cancer
Institute (NCI) in Bethesda, Maryland, has found that the natural
TCRs on T cells already resident in a tumor are often pretty
effective. In one experiment, they collected immune cells from a
patient’s tumor, grew them in culture, and selected the ones that
recognized cancerous cells. Then, they gave these chosen cells
back to the patient. Doing this, the group obtained “dramatic”
results with melanoma, says Stephanie Goff, a member of
Rosenberg’s team. Up to 70% of patients saw their tumor
load decrease substantially; in one trial, 40% had their tumors
disappear for at least five years after treatment.
Other roadblocks for CAR T-cell therapy
Researchers are also beginning to load their CAR T cells with
additional factors that should help them cut through the tumor
microenvironment. Brentjens, for example, has engineered CAR T
cells that make their own IL-12, which amplifies immune responses in a solid-tumor environment.
Yet another issue with CAR T-cell therapy is its personalized na-
ture. Making every batch of individualized T cells currently takes
“a lot of labor,” says Levine.
Cellectis thinks it has the answer to making off-the-shelf, universal CAR T-cell treatments, says Julianne Smith, vice president
of CAR-T development at the Paris-based company’s New York
City branch. The company uses gene editing, based on precisely
targeted transcription activator-like effector nuclease (TALEN)
enzymes, to delete part of the TCR complex from donor immune
cells, so they shouldn’t attack a new host. These CAR T cells will
eventually be rejected by the recipient, but Smith thinks they’ll
last long enough to perform their duty. The cells are in clinical
Back to the bench
The normal progression of biomedical science is to translate an
idea in the lab into a treatment in the clinic. But with so much
still unclear about how immunotherapies work, which approach to
take, and how to improve the available treatments, lab scientists
Researchers want to understand the tumor microenvironment,
and how a person’s microbiome might influence immunotherapy.
Moreover, they are eagerly searching for biomarkers that would
tell them if immunotherapy—which can take time to show definitive results—is working in a patient, says Jaffee. And they are
also poring over tissue samples from patients who were treated,
trying to differentiate those who respond to a given immunotherapy from those who don’t. That, says Kaufman, involves sequencing DNA and RNA, examining epigenetic markers, and visualizing
tissues via immunohistochemistry.
Nonetheless, immunotherapy has already handed cancer physi-
cians a powerful new weapon, not to mention an entirely new area
of biology to master. “The oncologists are becoming the new im-
munologists,” says Maher.
John Hopkins University
School of Medicine
King’s College London
Memorial Sloan Kettering
Amber Dance is a freelance writer living in Los Angeles.
Merck Research Laboratories
National Cancer Institute
Perelman School of Medicine,
University of Pennsylvania
San RaMaele University