Agilent - Breakthroughs in Immunotherapy- 2019 - 6

Breakthroughs in Immunotherapy * Interview with Dr. Carl June

a variety of ways compared to the natural
immune system. For a long time that was
a question - could that be done? Can you
improve upon a Darwinian, if you will, naturally evolved T cell, and if so can you do
that safely?
I think we've had more than 1,000 patients
treated with genetically engineered T cells,
primarily with cancer, and there have not
been any instances where the cells have
transformed or had evidence of genotoxicity. This is a major turning point, where
we have this orthogonal approach of
combining the knowledge of the entire
human genome and epigenome. We're
using that to look at vulnerabilities in the
tumor microenvironment and to make T
cells that are designed and "purpose-built"
to overcome the barriers that are in toxic
tumor microenvironments.
David Ferrick: How do you see the potential for engineering other immune cells,
such as natural killer cells (NKs), gamma
deltas, or macrophages?
Carl June: That's one of the reasons it's
so exciting to be in this field now. We
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realize that the immune system is not
just one instrument, to analogize, it's an
orchestra. They have non-overlapping roles
in the entire immune system. NK cells,
for instance, kill and recognize targets in
a way that is different from T cells. Similarly, there are subsets of T cells, gamma
delta cells that are more like an innate
immune cell, but they can also kill tumors.
They have a different metabolism and
can survive in different environments
in a better way than alpha beta T cells.
Because gamma delta cells don't have
alpha beta T cell receptors, they won't
cause graft versus host disease.
And recently macrophages have come to
the forefront, as they kill and eliminate cells
by phagocytosis rather than using a cytolytic mechanism like NK cells and T cells.
In addition, we'll see engineered stem cells
and their progeny, that after engraftment
into patients can produce engineered cells
of all the types we've just discussed.
David Ferrick: You've hit on an important
point, that the immune system is like an
orchestra, with homeostatic principles, and
there are many cell types that cooperate

in both time and space to achieve that.
One of the things we've focused on is the
advancement of cell analysis tools that can
generate information that is of a quality
[time-resolved] that can help to understand
this behavior along the timelines that occur
in vivo. Could you comment on the value of
real-time kinetic assays-let's call them the
'newer types' of cell-based solutions?
Carl June: That's a critical issue. The
emerging data in basic immunology is
showing that cells have major metabolic
reprogramming steps. Acute effector T
cells have, in general, dominant glycolysis for metabolism, whereas memory
cells proliferate slower but live longer, and
mostly use metabolism that's based on
fatty acid oxidation, Krebs Cycle, and mitochondrial biogenesis. From what we've
seen in mouse models of chronic infection
and tumors, you want to have populations of both cells. Some cells that would
be potent effector cells but are going to
be short-lived and another set of cells
that would be able to establish long-term
cellular memory and function, for long-term
immunosurveillance.
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