Medical Design Briefs - January 2024 - 32

60 days following the treatment, all animals
that received only FUS therapy had died,
while 75 percent of animals receiving only
the CDN-NP therapy were still alive - the
combination treatment allowed 100 percent
of animals in their group to survive.
FUS
thermal
ablation
CDN NPs
Single Molecule Arrays
(Simoa)
Immune Cells
Cancer Cells
Released cytokines/chemokines
The team engineered a strategy for monitoring the immunological responses to a newly devised, locally applied immunotherapy
against melanoma. (Credit: Wyss Institute at Harvard University)
The left microscopic image shows a magnified microneedle, and the right image a microneedle filled with a fluorescent
dye. (Credit: Wyss Institute at Harvard University)
cells. This CDN-NP therapeutic can be
directly injected in or close to cancerous
skin lesions to additionally increase the
drug concentration in tumors.
" Here, we chose to boost the processing
of antigens from dying tumor cells
following focused ultrasound together
with STING-agonist delivery in the
tumor microenvironment to coordinate
a broader immune response, " says
first-author Daniel Dahis, PhD. Dahis, is
a research scientist at the BioDevek startup
and performed his graduate work
32
on the study with Artzi while being cosupervised
by co-author Haim Azhari,
PhD, a professor at Technion Israel Institute
of Technology and an expert in
medical imaging.
The team first showed that the focused
ultrasound (FUS) treatment, which transiently
and in small areas increases the
temperature up to 60° C, potentiated the
effects of CDN-NP treatment in co-cultures
of immune and cancer cells in a dish, and
in melanoma tumors in mice, that they
treated with the combination. Importantly,
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n Tapping Deep into Skin Biomarkers
To investigate if the survival benefits
of the combination therapy are
mirrored in the levels of biomarkers
at the tumor site, which in the future
could translate to the monitoring of
responses in human patients treated
with immunotherapy, Artzi's group
had previously developed a novel type
of minimally invasive microneedles
that are made of hyaluronic acid and,
in principle, can be used to simultaneously
deliver drugs and detect
biomarkers. These devices reach into
the lower (dermal) layers of the skin
where the polymer encounters the
fluid surrounding skin cells, the socalled
interstitial skin fluid (ISF), and,
like a sponge, takes up tiny amounts
of it. " Merely a few microliters of ISF
obtained with microneedles provide
a wealth of biomarker information as
normal skin cells, local immune cells,
and cancer cells constantly secrete diverse
signaling molecules and metabolites, "
says Dahis. " After the microneedles
are retrieved, their tips can
be simply dissolved to release the captured
molecules into a test tube for us
to start the biomarker analysis. "
However, while the researchers saw
FUS clearly added to the immune response
evoked by CDN-NP in tumors,
many biomarkers of interest, including
genes that are switched on by the activated
STING protein, were barely detectable
or not detectable at all using
conventional methods. To overcome
this bottleneck, Artzi's team joined
forces with that of Wyss Core Faculty
member David Walt, PhD, who had previously
developed the Simoa technology,
which has ultrasensitive biomarker
detection abilities.
Co-author Tal Gilboa, PhD on Walt's
team, developed four Simoa assays to
detect
molecules whose
expression
is activated by STING: interferon-b
(IFN-b), MCP-1 and KC, which both
attract immune cells to tumors, as well
as the general inflammation marker interleukin-6
(IL-6). Indeed, this enabled
the researchers to detect these bioMedical
Design Briefs, January 2024
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Medical Design Briefs - January 2024

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