IsoPlexis Roundtable/Literature Review - 5

EXPERT PANEL DISCUSSION
cancer the state of the art in biomedicine, leading
virtually every other kind of biomedicine out there.
The challenge is that you have got to be careful what
you ask for, because this is expensive. So, finding ways
to really democratize these technologies to make them
not just fast-and I think if you make them fast, you
are going to make them cheaper; those two go together-is a really important research problem.
There is almost anything you can look at the singlecell level now. You can look at the epigenome. You
can look at the genome. You can look at the transcriptome. You can look at secreted proteins. All of
these are slowly turning into sequencing assays. No
matter what the analyte you are measuring, they are
turned into sequencing assays. You know, we are able
to do these things in situ and in tissue, and to connect to
blood. But it is just crazy expensive.
One of the major advances that we need to come up
with as practitioners in this field is, how do you make it
cheaper? How do you make it so that it is a type of
analysis that can lead to improved therapies and is
available to broader classes of patients? And then you
are going to be able to do population studies in a way
that is going to allow you to discover more, as well, by
being able to democratize those technologies.
Dr. Merghoub: And I would add to that, since we are
in the wish lists, how can you make it on banked
material? For example, if we were able to do single
cell on frozen samples, that would be amazing.
Dr. Daver: Yeah, I think that single cell is going to
come. We have done a lot of molecular single-cell
DNA analyses for mutation tracking, and the information you get is just amazing, and it is extremely
different from what we may have assumed to be the
patterns of clonal escape or resistance.
A specific example I will give you is with minimal
residual disease in leukemias, wherein we usually
would just do it based on multiparametric flow cytometry for many years, and we knew there was some
minimal residual disease. It was like whack-a-mole,
you know, take an agent to target MRD and hope it
works.
But now, with single-cell DNA sequencing, we are
able to really pick up which particular clone is
emerging as the driver of resistance very very early,
which means then we can pick the right drug for that
clone. And now there are trials being set up using this
approach that I think will really push the field forward.
The same is happening in solid tumor.
So, I think it will come. The quicker we can get it,
the better, because I think this is so much more informative than bulk sequencing, which was helpful,
but in the end, you had to make a guess and take a drug
and hope that it was kind of working in that group.
ª 2020 by Mary Ann Liebert, Inc.

Dr. LeMieux: Okay, so how does cell heterogeneity
play a role in patient relapse, and how does that
inform the development of cancer immunotherapies
to address challenges like this?
Dr. Butterfield: We keep mentioning that this is one
of the most critical hurdles we have, and a driver of
both our biomarker searches and our therapeutic
searches and our ability to assess it by getting sufficient tumor specimens or understandable liquid biopsies to know the way to direct those efforts.
Dr. LeMieux: What are the novel strategies being
used to overcome challenges such as antigen escape?
Dr. Merghoub: When you have a heterogeneous tumor, basically, you have subsets of cells that have
some differences genetically, and that will allow that
tumor to resist a given treatment, because they have
the antigen that you are targeting, for example, if you
are using a CAR T cell therapy, wherein we are targeting one antigen.
Having multipronged approaches would allow you
to attack the tumor from multiple angles-meaning
that if you are looking at antigen, you need to be able to
elicit a response against multiple antigens. So, if you
have one antigen escape variant, then you still have the
other antigens, for example. But it all lies into understanding what type of heterogeneity you have. So, you
are able to develop means to target multiple targets, so
to speak.
Dr. Heath: I think also, if you have a properly functioning immune system in the tumor, it is actually
pretty hard for tumors to exhibit antigen escape unless
they turn the T cells off. And when you see a successful checkpoint immunotherapy, you will see many
T cell populations against different tumor antigens that
are emerging or evolving over time in a way that sort
of signifies that you have generated at least a somewhat robust antitumor response.
Dr. Merghoub: One of the examples, in terms of immune escape, is when you turn off the MHC presentation machinery. So, if you have a mutation in the antigen
presentation machinery, then the immune system is
blind to that tumor. We need to trigger, for example, an
innate response that would eliminate the tumors.
And some of the work we have done in the laboratory, for example proposing eliciting neutrophils,
could be a second wave of cells that would come in and
will indiscriminately eliminate the cells that have lost
MHC expression.
Dr. Heath: There may be epigenetic approaches to
retain MHC expression.
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