616 7 FEBRUARY 2020 • VOL 367 ISSUE 6478 sciencemag.org SCIENCEIMAGE: STEVE GSCHMEISSNER/SCIENCE SOURCEL
aunching a new chapter in the fast-
moving cancer immunotherapy field,
scientists have blended two cutting-
edge approaches: CRISPR, which
edits DNA, and T cell therapy, in which
sentries of the immune system are ex-
ploited to destroy tumors. Two women and
one man, all in their 60s—one with sarcoma
and two with the blood cancer multiple
myeloma—received CRISPR-altered versions
of their own cells last year, researchers re-
port online in Science this week.
For these pioneers, the benefits were lim-
ited: One has since died, and the disease
has worsened in the others. But the clinical
trial, which underwent years of regulatory
scrutiny, wasn’t designed to try to cure can-
cer, says Carl June, a cancer researcher at
the University of Pennsylvania (UPenn) who
co-led the work. Rather, its goal was to show
that the strategy appeared feasible and safe.
By that measure, scientists agree, it suc-
ceeded. “This is a Rubicon that has been deci-
sively crossed,” says Fyodor Urnov, a genome
editor at the University of California (UC),
Berkeley. The study, he says, the first of its
kind in the United States, answers “questions
that have frankly haunted the field.”
The researchers used CRISPR alongside
another strategy that incorporates new
DNA into immune cells. June’s team helped
pioneer that strategy in 2010, when it added
DNA to T cells from three men with chronic
leukemia and returned those cells to thepatients. The results were remarkable: Two
men are still alive and healthy today. Others
were testing the same approach, called CAR-
T cell therapy—after the inserted chimeric
antigen receptor gene that helps the infused
T cells latch onto and destroy cancer cells
with a specific protein on their surface. Two
CAR-T cell therapies are now approved for
patients with leukemia and lymphoma.
But with time, the therapy’s limitations
have come into focus. Not every cancer pa-
tient is helped, and even those who are can
suffer a relapse, says Edward Stadtmauer,
who treats blood cancers at UPenn and co-led
the new study. And solid tumors like those in
the brain and pancreas have proved tough to
treat (Science, 2 September 2016, p. 983).
Using CRISPR to knock out selected genes
while also adding DNA, it was hoped, might
make T cells even more powerful and persis-
tent. But CRISPR brought its own uncertain-
ties. Lab studies have revealed “off-target”
effects, in which unintended DNA gets modi-
fied. No one knew whether T cells with sliced
and diced genes could even survive in the
human body. Last year, Vertex Pharmaceu-
ticals and CRISPR Therapeutics announced
that two patients treated for inherited blood
diseases with CRISPR-edited cells were doing
well. But details were sparse.
June, Stadtmauer, and their colleagues
began by hunting for patients whose tu-
mors produced a protein called NY-ESO-1,
a target for the gene the researchers would
add to their T cells. The patients also
needed to carry a specific version of hu-man leukocyte antigen, an immune gene
complex that could help the infused T cells
flourish. The four patients who qualified
were all extremely ill, as is the norm for
such a novel therapy. A woman with mul-
tiple myeloma had undergone three bone
marrow transplants. Another, in her late
30s with sarcoma, became too sick to treat
while her cells were being prepped in the
lab, a process that takes 4 to 6 weeks. She
entered hospice care and died.
To try to rev up the patients’ T cells against
their disease, the scientists used CRISPR to
knock out two genes that encode what’s
known as the T cell receptor. The group also
crippled a third gene, for a protein called PD-- PD-1 puts the brakes on immune responses,
and eliminating its effects, June’s team theo-
rized, might enrich the T cells’ powers. Then,
they inserted the gene for a different T cell
receptor that would target NY-ESO-1.
Intensive monitoring of the patients, in-
cluding blood draws to study their altered T
cells, confirmed that CRISPR had left some
off-target changes. But they were few, and the
number of cells with these unintended DNA
changes faded over time. Encouragingly,
the CRISPR-edited cells persisted at least
9 months—versus about 2 months in com-
parable CAR-T cell therapy studies. Imaging
showed “beautiful, healthy T cells,” June says,
that in lab studies beat back cancer months
after they’d been infused.
But in patients, outcomes were modest.
The best response was in the sarcoma pa-
tient, whose primary tumor shrank, though
his cancer later progressed. “It wasn’t like
you turned off those genes and those T cells
started doing things that were amazing,”
says Antoni Ribas, an oncologist at UC Los
Angeles. Ribas, June, and others offer po-
tential reasons, including the small number
of patients treated, possible limitations of
NY-ESO-1 as a target—selected in part for
its safety record—and the failure to knock
out all three genes in many of the cells.
Some of the authors are working with
companies to commercialize the method.
But much experimentation lies ahead. “This
whole area is just teeming with different
ideas,” Stadtmauer says. A handful of other
trials, including several in China, are offering
CRISPR-modified cells to patients with can-
cer or other diseases. A company called PACT
Pharma, which Ribas helped found, is run-
ning a trial that uses CRISPR to target gene
mutations within solid tumors.
What June’s group offers is “a needed start”
for giving patients CRISPR-edited T cells,
Ribas says. From now on, he adds, “It’s going
to be easier—because they did it first.” j
CRISPR takes on cancer
Gene edits appear safe in first three patients
BIOMEDICINEImmune cells (brown) attack a cancer cell. Using
CRISPR could make the immune cells more potent.By Jennifer Couzin-FrankelPublished by AAAS