Agilent - Breakthroughs in Immunotherapy- 2019 - 19

Breakthroughs in Immunotherapy

RTCA assay, target cell proliferation and
killing by effector cells can be monitored
at lower effector to target ratios. These
low ratios more closely mimic physiological conditions, which may better
predict patient response. Researchers can
also use reduced concentrations of the
precious cells in the assays, allowing them
to simultaneously test more conditions.
"The high throughput xCELLigence RTCA
assay can measure cell killing continuously, which makes it an excellent
functional potency assay. For INKmune,
target cells resistant to NK killing are
grown in the xCELLigence E-plate, then
pooled donor NK cells are added to show
nothing happens. Twenty-four hours later,
INKmune is added, and, if it is functional,
the NK cells get switched on and a change
occurs in the target cell cytotoxicity in the
next five days," explains Dr. Lowdell.

Cell-Based Assays versus
Animal Studies
Animal studies are often complex, lengthy,
and expensive. They may not be reflective or
predictive of the human patient or disease
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process, and there simply may be no good
animal model. "In the manufacturing of cell
therapies, potency assays cannot be animal
studies," indicates Dr. Roy. "Cell-based in
vitro assays are a surrogate to determine
cell function. The more the human disease
can be mimicked, the better the in vivo
predictions. As better in vitro assays are
developed they will play a significant role
during the manufacturing process."
A critical fundamental issue with animal
studies is the difference in homology
between human and other mammalian cells. When human effector cells are
injected into the bloodstream of a patient,
they bind to specific molecules in the
tumor microenvironment to activate an
immune response, which leads to target
tumor cell killing. When these human
effector cells are injected into a rodent
used for animal studies, the binding
between human effector cells and rodent
ligands may not be predictive of the
killing activity in a human tumor
microenvironment.
Another challenge with animal studies is
the enhanced immune response observed

when a tumor is artificially established
in an animal model. Typically, a rapidly
dividing tumor cell line is injected into the
animal, creating a lump. Subsequently,
this tumor creates an acute inflammatory response. In patients, a tumor is part
of a chronic immune response due to the
localized tumor microenvironment and its
immunosuppressive nature. Acute and
chronic inflammatory responses lead to
different immunological outputs, so the
immune response observed in an animal
model may not be indicative of the product
potency and efficacy in patients.
According to Dr. Lowdell, "the UK regulatory board was excited to see a dynamic
model of a tumor growing without a local
inflammatory response using the xCELLigence RTCA instrument. I believe real-time
assays are going to be increasingly used
both in drug development and manufacturing as a potency or release assay."

Screening for Safety
Screening for contamination and sterility
is routine but other safety screens are
challenging; the understanding of how a
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Agilent - Breakthroughs in Immunotherapy- 2019

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