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Construction and evaluation of a novel humanized HER2-specific chimeric receptor.
[severe combined immunodeficiency]
The
human
epidermal
growth
factor
receptor
2
(
HER
2
)
represents
one
of
the
most
studied
tumor
-associated
antigens
(
TAAs
)
for
cancer
immunotherapy
.
The
monoclonal
antibody
(
mAb
)
trastuzumab
has
improved
the
outcomes
of
patients
with
HER
2
+
breast
cancer
.
However
,
a
large
number
of
HER
2
+
tumors
are
not
responsive
to
,
or
become
resistant
to
,
trastuzumab-based
therapy
,
and
thus
more
effective
therapies
targeting
HER
2
are
needed
.
H
ER
2
-
specific
T
cells
were
generated
by
the
transfer
of
genes
that
encode
chimeric
antigen
receptor
(
CAR
)
.
Using
a
multistep
overlap
extension
PCR
method
,
we
constructed
a
novel
,
humanized
HER
2
CAR-containing
,
chA
21
single
-chain
variable
fragment
(
scFv
)
region
of
antigen-
specific
mAb
and
T
-
cell
intracellular
signaling
chains
made
up
of
CD
28
and
CD
3
ζ
.
An
interferon
γ
and
interleukin
2
enzyme-linked
immunosorbent
assay
and
a
chromium-
51
release
assay
were
used
to
evaluate
the
antitumor
immune
response
of
CAR
T
cells
in
coculture
with
tumor
cells
.
Furthermore
,
SKBR
3
tumor
-bearing
nonobese
diabetic
/
severe
combined
immunodeficiency
(
NOD
/
SCID
)
mice
were
treated
with
HER
2
CAR
T
cells
to
evaluate
antitumor
activity
.
Human
CD
3
+
T
cell
accumulation
in
tumor
xenograft
was
detected
by
immunohistochemistry
.
chA
21
-
28
z
CAR
was
successfully
constructed
,
and
both
CD
4
+
and
CD
8
+
T
cells
were
transduced
.
The
expanded
HER
2
CAR
T
cells
expressed
a
central
memory
phenotype
and
specifically
reacted
against
HER
2
+
tumor
cell
lines
.
Furthermore
,
the
SKBR
3
tumor
xenograft
model
revealed
that
HER
2
CAR
T
cells
significantly
inhibited
tumor
growth
in
vivo
.
Immunohistochemical
analysis
showed
robust
accumulation
of
human
CD
3
+
T
cells
in
regressing
SKBR
3
lesions
.
The
results
of
this
study
show
that
novel
chA
21
scFv-based
,
HER
2
-
specific
CAR
T
cells
not
only
recognized
and
killed
HER
2
+
breast
and
ovarian
cancer
cells
ex
vivo
but
also
induced
regression
of
experimental
breast
cancer
in
vivo
.
Our
data
support
further
exploration
of
the
HER
2
CAR
T
-
cell
therapy
for
HER
2
-
expressing
cancers
.
Diseases
Validation
Diseases presenting
"breast cancer in vivo"
symptom
severe combined immunodeficiency
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