IsoPlexis Roundtable/Literature Review - 3

EXPERT PANEL DISCUSSION
trial. We also still need functional assessments. We
can get molecular profiles, but without knowing much
protein-level function and what that means. That is
another critical need.
Dr. Merghoub: The most useful thing is to understand
what the intrinsic mechanism of the tumor is itself and
differentiate it from the tumor microenvironment. So,
it can probably give you some hints of the tumor cell
itself, but not the tumor microenvironment as it is now.
And I agree that as we learn how to probe the peripheral tissues, we will be better at it.
Dr. Daver: Also, there is a gap. For example, with
whole-exome sequencing. There are articles on wholeexome sequencing from 30 years ago. But it was not
something that was scalable and still is not fully
scalable in the clinical practice.
There is a difference between what can be done in a
small biological experiment in a focused research
setting and what you can do on a routine clinical
practice. And that may be where the gap is. It may be
possible, but it is not yet practical.
We are getting better. We are now able to do advanced analyses with modalities such as flow, and
beyond that with CyTOF, mass cytometry, where we
can look at more markers on different T cell populations. We can do some functional assays on some of
the T cells.
But a lot of the data in the clinical sector are really
still based on structural assessment of tumor biopsies,
mainly numerically counting T cells and then assessing different checkpoint expressions by immunohistochemistry and flow. It is going to take some time
before the science catches up into the clinical practice.
Dr. LeMieux: What are the limitations of the current standard methods for evaluating the mechanisms related to persistence, suppression, and
resistance within the tumor-immune interactions
with patients?
Dr. Daver: This is one of the big challenges we have.
We are working with a number of different trials with
immune checkpoints, bispecific antibodies, and vaccines. Chimeric antigen receptor T (CAR T) cells, of
course, in leukemia are very very big and very effective across a number of different CAR constructs. And
most of our analyses in the immunological sphere in
the patient setting have really been about what is the
degree of T cell infiltration in a given tumor.
What has been lacking has been functional assessment that is very difficult to do in a routine clinical
setting.
One of the technologies we have done on some of
our trials is using single-cell cytokine production in
ª 2020 by Mary Ann Liebert, Inc.

collaboration with IsoPlexis, which has shown some
interesting early signals in CAR T cells as well as in
immune checkpoints, where we can assess the baseline
functionality of T cells and the diversity and the
quantity of cytokines they are able to generate and we
have seen some strong correlations with this baseline T
cell functionality and clinical response. But I think,
again, this is not something yet widely usable in the
clinic-so we still lack functional measures for immune activity outside of clinical trials and research
efforts.
Dr. Merghoub: I totally agree. I think that in any
setting, people mainly do studies of phenotypes, but
we do not know whether that phenotype equates
function.
A typical example is when we look at suppressive
populations, but we do not know whether it is a real
suppressive population in that context, or it just has a
landmark of the suppressive population. If we are able
to assess the functionality of these cell populations and
the relationship between each other, I think we will be
in a better place.
Dr. LeMieux: What types of biomarkers are needed
to better define the biological drivers of antitumor
response, overcoming resistance and other immune
functions that dictate patient outcome?
Dr. Heath: This really depends upon the therapy
modality. If you went back 10 years, when targeted
inhibitors were having their initial heyday, there were
a lot of similar discussions as we are having now-
without nearly the number of tools. And then there was
the significant breakthrough of CAR T cells and
checkpoints and those things changed the landscape.
If you are thinking about cell-based therapies, that
would go beyond CAR T cells, and I think you really
want to have a strong grip on what are the truncal
antigens that are associated with the tumor? And that is
going to be things that are both from somatic mutations and by experience in things like this. We are just
now beginning to get a feeling for some of those. That
is something in principle you can measure out of the
blood.
And then you have got these epigenetic mechanisms
of resistance. Well, there is a host of new epigenetic
drugs that are coming along that are very likely to
change the landscape of what we need and do not need.
But in principle, those also-the epigenetic targets-
can in principle be extracted from the blood through
various ataxic and other chromatin-like-associated
measurements.
This field is changing. It has changed dramatically
quickly over the past 20 years. And the picture of what
you need or do not need in terms of measurements
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