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SUNDAY SCIENCE: HOW TO SUPERCHARGE CANCER-FIGHTING CELLS – GIVE
THEM STEM-CELL SKILLS  
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Sara Reardon
April 10, 2024
Nature [[link removed]]

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_ The bioengineered immune players called CAR T cells last longer and
work better if pumped up with a large dose of a protein that makes
them resemble stem cells. _

A CAR T cell (orange; artificially coloured) attacks a cancer cell
(green). , Eye Of Science/Science Photo Library

 

Bioengineered immune cells have been shown to attack and even cure
cancer [[link removed]], but
they tend to get exhausted
[[link removed]] if the fight
goes on for a long time. Now, two separate research teams have found a
way to rejuvenate these cells: make them more like stem cells
[[link removed]].

Both teams found that the bespoke immune cells called CAR T cells
[[link removed]] gain new vigour
if engineered to have high levels of a particular protein. These
boosted CAR T cells have gene activity similar to that of stem cells
and a renewed ability to fend off cancer
[[link removed]]. Both papers were
published today in _Nature_1
[[link removed]],2
[[link removed]].

The papers “open a new avenue for engineering therapeutic T cells
for cancer patients”, says Tuoqi Wu, an immunologist at the
University of Texas Southwestern in Dallas who was not involved in the
research.

Reviving exhausted cells

CAR T cells are made from the immune cells called T cells, which are
isolated from the blood of person who is going to receive treatment
for cancer or another disease. The cells are genetically modified to
recognize and attack specific proteins — called chimeric antigen
receptors (CARs) — on the surface of disease-causing cells and
reinfused into the person being treated.

But keeping the cells active for long enough to eliminate cancer has
proved challenging, especially in solid tumours
[[link removed]] such as those of
the breast and lung. (CAR T cells have been more effective in treating
leukaemia and other blood cancers.) So scientists are searching for
better ways to help CAR T cells to multiply more quickly and last
longer in the body.

With this goal in mind, a team led by immunologist Crystal Mackall at
Stanford University in California and cell and gene therapy researcher
Evan Weber at the University of Pennsylvania in Philadelphia compared
samples of CAR T cells used to treat people with leukaemia1
[[link removed]].
In some of the recipients, the cancer had responded well to treatment;
in others, it had not.

The researchers analysed the role of cellular proteins that regulate
gene activity and serve as master switches in the T cells. They found
a set of 41 genes that were more active in the CAR T cells associated
with a good response to treatment than in cells associated with a poor
response. All 41 genes seemed to be regulated by a master-switch
protein called FOXO1.

The researchers then altered CAR T cells to make them produce more
FOXO1 than usual. Gene activity in these cells began to look like that
of T memory stem cells, which recognize cancer and respond to it
quickly.

The researchers then injected the engineered cells into mice with
various types of cancer. Extra FOXO1 made the CAR T cells better at
reducing both solid tumours and blood cancers. The stem-cell-like
cells shrank a mouse’s tumour more completely and lasted longer in
the body than did standard CAR T cells.

Master-switch molecule

A separate team led by immunologists Phillip Darcy, Junyun Lai and
Paul Beavis at Peter MacCallum Cancer Centre in Melbourne, Australia,
reached the same conclusion with different methods2
[[link removed]].
Their team was examining the effect of IL-15, an immune-signalling
molecule that is administered alongside CAR T cells in some clinical
trials. IL-15 helps to switch T cells to a stem-like state, but the
cells can get stuck there instead of maturing to fight cancer.

The team analysed gene activity in CAR T cells and found that IL-15
turned on genes associated with FOXO1. The researchers engineered CAR
T cells to produce extra-high levels of FOXO1 and showed that they
became more stem-like, but also reached maturity and fought cancer
without becoming exhausted. “It’s the ideal situation,” Darcy
says.

The team also found that extra-high levels of FOXO1 improved the CAR T
cells’ metabolism, allowing them to last much longer when infused
into mice. “We were surprised by the magnitude of the effect,”
says Beavis.

Mackall says she was excited to see that FOXO1 worked the same way in
mice and humans. “It means this is pretty fundamental,” she says.

Engineering CAR T cells that overexpress FOXO1 might be fairly simple
to test in people with cancer, although Mackall says researchers will
need to determine which people and types of cancer are most likely to
respond well to rejuvenated cells. Darcy says that his team is already
speaking to clinical researchers about testing FOXO1 in CAR T cells
— trials that could start within two years.

And Weber points to an ongoing clinical trial in which people with
leukaemia are receiving CAR T cells genetically engineered to produce
unusually high levels of another master-switch protein called c-Jun,
which also helps T cells avoid exhaustion. The trial’s results have
not been released yet, but Mackall says she suspects the same system
could be applied to FOXO1 and that overexpressing both proteins might
make the cells even more powerful.

_doi: [link removed]

References

*
Doan, A. _et
al._ _Nature_ [link removed] (2024).

Article [[link removed]] Google Scholar
[[link removed].] 

*
Chan, J. D. _et
al._ _Nature_ [link removed] (2024).

Article [[link removed]] Google Scholar
[[link removed].] 

_SARA REARDON: I’m a freelance journalist covering biomedical,
environmental and social science from beautiful Bozeman, Montana. I've
previously  worked as a staff reporter at Nature, New
Scientist and Science. In my previous life, I studied mouse sperm
and retinas. Realizing that I could never limit my interests to one
field of science, I switched to science journalism -- a field that
thrills me every day. I've reported from five continents and all over
the United States. My favorite stories involve the myriad ways in
which science intersects with society, particularly through law,
ethics, and culture. I also make short films about science and
health-related issues affecting my local community. Follow me on
Twitter [[link removed]] to see my latest
work and drop me a message
[[link removed]] if you have ideas
or tips! _

_NATURE is a weekly international journal publishing the finest
peer-reviewed research in all fields of science and technology on the
basis of its originality, importance, interdisciplinary interest,
timeliness, accessibility, elegance and surprising
conclusions. Nature also provides rapid, authoritative, insightful
and arresting news and interpretation of topical and coming trends
affecting science, scientists and the wider public._

_Nature's mission statement_

_First, to serve scientists through prompt publication of significant
advances in any branch of science, and to provide a forum for the
reporting and discussion of news and issues concerning science.
Second, to ensure that the results of science are rapidly disseminated
to the public throughout the world, in a fashion that conveys their
significance for knowledge, culture and daily life.
Nature's original mission statement
[[link removed]] was
published for the first time on 11 November 1869._

_About the Editors_

_Like the other Nature titles, Nature has no external editorial
board. Instead, all editorial decisions are made by a team of
full-time professional editors. Information about the scientific
background of the editors
[[link removed]] may be found here._

__

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Together
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Stanley J. Brodsky, Alexandre Deur, Craig D. Roberts
Scientific American
April 12, 2024

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