IsoPlexis Roundtable/Literature Review - 2

EXPERT PANEL DISCUSSION
Dr. LeMieux: How do the challenges of interrogating the tumor-immune interaction play a role in
cancer immunology and developing new therapies?
Dr. Butterfield: Tumor heterogeneity is one of the
key hurdles and being able to obtain surgical biopsies
remains a challenge. We can get cores for molecular
work, but really interesting tumor-immune interactions require biopsies of the tumor that enable us to
understand the heterogeneity around the infiltrate,
around the tumor antigen expression, and other drivers
of the tumor in situ.
Dr. Merghoub: I agree. It is important to determine
the immune driver for the immune response, and, in a
given setting, to try to understand what is specific to
the organ or the tissue where the tumor is happening.
Also, understanding what changes are due to the
context that would lead to tumor control or immune
escape would really benefit from having access to tumor biopsies in real time and at multiple time points
during the treatment.
That would be the ideal. It would also be good if we
were able to translate what we see in the tumor microenvironment in places that are more accessible,
such as blood, for example-if that was able to tell us
what is happening in the tumor microenvironment.
That would help us have a more personalized approach
based on each patient's response to these therapeutic
modalities.
Dr. Daver: Each tumor has a different sensitivity
profile, and within each tumor type, each patient has
different sensitivity profiles. So initially, when we saw
these breakthroughs with melanoma, lung cancer,
there was hope that maybe drugs such as immune
checkpoints could work across all tumors.
We are seeing now, over time, that that is not true.
There are certain tumors that do not have a very good
response to single-agent immune checkpoint and may
need combinations or other modalities such as bispecifics.
Understanding, before treating an individual patient,
what is the immune infiltration, what are the nature of
T cells, what is the function of those T cells, and what
are the hurdles to those T cells functioning may help us
really select optimal therapies, or not select an immune
therapy in certain patients wherein other molecular or
chemotherapies may be effective.
Dr. Heath: There are a bunch of modern methods for
tumor analysis wherein you can, with spectacular
precision, look at tumor cells and local immune cells
and get a very very deep analysis of them.
And if you do a comparison using those tools,
maybe even getting entire transcriptomes of cells in2

side that environment, and you look at a tumor like
melanoma compared with a more challenging tumor-
you find that there are very striking differences, and
you find that you can come up with hypotheses for how
you might more effectively treat these more challenging tumors with additional checkpoints or what
have you.
But again, all these are requiring that you have the
tumor. And what you really would like to do is to look
in the blood and get that same information. To be able
to design custom personalized therapies, I think the
whole world knows that that is where we are going. To
be able to pull that information out of the blood is
really probably one of the grand challenges, rather
than just doing it out of the tumor.
Dr. LeMieux: What advanced analytics specific to
cancer immunology are needed for accelerated insights into this therapeutic development?
Dr. Heath: We also have a host of different resistance
mechanisms, or therapy evasion mechanisms, that
happen within the tumor. Some are adaptive ones or
ones that have become very well studied over the past
few years. But before then it was more Darwinian-type
selection. Both of those things are operational in many
tumors. Adaptive means that the same cells you are
drugging actually develop resistance by undergoing
cell state changes.
Those can be important for immunotherapy because
you can lose MHC expression or factors like that. And
once again, in principle, one should be able to look in
the blood and at least see signatures of this kind of
thing. But right now, we do not have that capability.
We are barely beginning to understand the tumor itself
in the context of some of these mechanisms.
Extracellular vesicles are incredibly promising, because they contain genetic material from the tumor.
But you have got somewhere around a billion of them
and a very small amount of blood, and you do not
know which tissues they are coming from, and so you
have got a very heterogeneous production and distribution of these throughout the blood. People are just
now beginning to think about how to pull that information out. And I do think, ultimately, you will be able
to get as much out of the blood as you want, but the
analytical capacities are now quite a bit behind where
they ultimately need to be.
Dr. Butterfield: I think we will find everything in the
blood. We just do not know yet what we are looking
for. We are in a discovery phase for a lot of these
things, and we can make terrific insights, but we are
not yet in a reproducible standardized place where we
can apply some assay to an outbred human patient
population and learn something actionable out of a
ª 2020 by Mary Ann Liebert, Inc.

IsoPlexis Roundtable/Literature Review

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