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 "The findings represent an important advance in the therapeutic
application of gene editing and highlight the potential to
accelerate development of cell-based therapies," Jennifer Doudna of
the University of California at Berkeley, who pioneered the gene
editing technique, and her colleague Jennifer Hamilton write in an
editorial.
The CRISPR approach has quickly become the preferred method of gene
editing in research labs because of its ease of use compared with
older techniques, and doctors have begun testing it to treat a
number of diseases.
CRISPR-Cas9, used in this study, works like a pair of molecular
scissors that can target and trim away parts of the genome and
replace them with new stretches of DNA.
CRISPR has already shown promise at editing the genes of patients
with beta thalassemia and sickle cell disease in clinical trials.
In the latest study, Dr. Edward Stadtmauer of the University of
Pennsylvania in Philadelphia and colleagues tested it in three
patients with advanced cancers. Two had the blood cancer multiple
myeloma and one had sarcoma, a cancer that attacks connective
tissues.
The researchers paired the use of CRISPR with a type of
immunotherapy in which scientists harvest T-cells from a patient's
immune system, reprogram them to attack cancer cells and infuse them
back into patients.
Engineered T cell therapies, such as CAR-T therapy (or chimeric
antigen receptor T cell therapy), can produce long-lasting remission
in patients with blood cancers. But the treatments don't work for
many other kinds of cancer, the immunity can wane and they can cause
serious side effects.
Stadtmauer and colleagues sought to use CRISPR to address some of
those issues. They took immune system cells from the patients' blood
and used the CRISPR-Cas9 system to delete genes from the cells that
might hamper the immune system's ability to fight cancer, and
engineered the cells to recognize and attack cancer cells.
The team then infused these cells back into the patients and watched
to see if they would multiply. So far, the researchers have not seen
any toxic side effects. The engineered T-cells started growing in
all of the patients and lasted for up to nine months after the
infusion.
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"Until now, it has been unknown whether CRISPR-Cas9 edited T cells
would be tolerated and thrive once reinfused into a human," Doudna
writes. "The big question that remains unanswered by this study is
whether CRISPR-edited, engineered T cells are effective against
advanced cancer."
The pilot study was designed to track safety. Larger trials will be
needed to test for efficacy. At the end of the trial, one patient
died from advanced cancer, and the other two were receiving other
treatments.
A key concern with CRISPR-edited cells is that the technique has
been shown to create some "off-target" or unintended edits in the
genome.
Study co-author Dr. Carl June, an immunologist at the University of
Pennsylvania who pioneered CAR-T cell therapy, said the team found
two off-target effects.
One was a rare change in the DNA code that occurred in 1 in 1,000 of
the edited cells. The other was a chromosome translocation, in which
a chromosome reattached itself to the wrong chromosome. This
occurred in fewer than 1.5 percent of the infused cells, June said
in an email to Reuters Health.
The infused cells with these unintended edits did not survive as
well as the correctly edited genes, he said.
Based on the promising safety profile, June said it's likely that
many academic centers and companies will try the technique in
further clinical trials.
"We hope to work with companies to advance this but at this point,
there are no firm plans," he said.
SOURCE: http://bit.ly/3bjFKU3, http://bit.ly/2v9MALe and http://bit.ly/3bhdCkj
Science, online February 6, 2020.
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