Horizon eBook - 2020 - 25

Engineering the Immune Response For Therapeutic Success

Our customers asked us to develop CRISPR screens that use
primary cells to improve their drug discovery outcomes. Because
primary cells are closer to a patients' cells, the screens can identify
targets that could be more relevant to the clinic. By contrast,
screens of continuously cultured cancer cell lines
that have mutated and adapted to grow in culture
medium might give skewed results compared with
healthy tissue.

How were these screens developed?

McCARTHY: When I started working on CRISPR-Cas9 screening
with the immunology team three years ago, we started with primary
T cells. We made this choice because our CRISPR
libraries are lentivirus-based, and we knew that this
cell type could be infected with a lentivirus; we
believed this would be a straightforward way to
begin the project. But it turned out to be harder than
What has changed in primary T cell work?
we thought. For some reason-and we are still not
clear why-delivering Cas9 to primary T cells using a
McCARTHY: Our work in primary T cells has
lentivirus vector was very challenging. Other groups
been helped by advances in the cell therapies
have found this challenging as well. Further work
that have now made it into patients. Companies
showed that we could deliver Cas9 mRNA using
and researchers developing adoptive T cell and
electroporation, and so we created a dual system,
Nicola McCarthy, Screening Business Unit
CAR-T cell therapies have found ways to keep
using both the lentivirus and the electroporation
Manager, Horizon Discovery Group
autologous and allogeneic cells alive in culture
technology as a workaround. All in all, it took two and
long enough for manipulation, expansion and delivery to the
a half years of research. In January 2019, Horizon Discovery's Screening
patient. These technologies and techniques that allow cell
Unit extended its CRISPR screening service to include ex vivo T
therapies to move from bench to bedside are now returning
lymphocytes for immunology-based research in drug discovery.
to the bench and being used in new applications for in vitro
screening. The biggest changes have been in the improvements
How did you validate your approach?
in culture media and the commercial availability and ease of use
of the antibodies required to activate the T cells as part of the
McCARTHY: To check that our primary cell screen is not missing
screening process.
anything that screens in cancer cell lines can find, we carried out a
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Horizon eBook - 2020

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