IsoPlexis Roundtable/Literature Review - 7

EXPERT PANEL DISCUSSION
You just need to push them along. Single-agent
checkpoint therapy may be sufficient in such cases.
But there may be others wherein you do not have that
degree of T cell infiltration/activation, and maybe you
need to have double-checkpoint. And it may be two
different double-checkpoints-PD1, CTLA4, TIM33,
LAG-3, and ICOS. There is a whole host of them, and
we know that different patients are using different
double-checkpoints for tumor evasion.
And then there may be some patients who have really really immune-depleted or immune-desert kind of
tumors, where then the question really is whether
immunotherapy is the optimal choice, or maybe we
want to use some other modality of therapy?
Knowing the functionality and then correlating this
in clinical trials going forward, and if we can use the
pre-existing T cell functionality to select optimal
single-agent or combination or nonimmunotherapy
approaches would be wonderful in the clinical setting
for us to avoid additional toxicities or waste time with
a treatment that may not be optimal in a given patient.
Dr. LeMieux: If you could pinpoint one aspect, or
one area, that has impacted the field of cancer the
most over the past 20 years, what would it be?
Dr. Heath: I would say that the success of immunotherapy has had the most profound change. And the
reason I would say that is because one can look at
almost any cancer, any patient now, and come up with
a hypothesis for how you might treat them. It does not
mean it would be successful. It does not mean you
have the drugs now. But you could have a hypothesis
based upon harnessing the immune system that could
treat that tumor and the distant metastases, etc., that
you might want to do.
I do not think that was true before. I would look at
that as a conceptual change. But that drives a lot of the
tech development in terms of looking at all the heterogeneity and the immune system, the functionality
of the immune system, etc. It drives a lot of ways of
thinking about how to bring new technologies to bear
to test those hypotheses in preclinical settings and
advance them. It is a conceptual advance that simply
was not there 20 years ago, and flavors almost every
conversation about oncology today.
Dr. Butterfield: I started in cancer vaccination about
25 years ago, and when I went to my first AACR
meeting, I was so enamored with immunotherapy. I
could not believe that when I put my poster up, there
were only two rows for immune anything, and everything else was chemo and radiation. I could not
believe anyone would do anything toxic when the
promise of immunotherapy was so wonderful. But it
just did not have any clinical data.
ª 2020 by Mary Ann Liebert, Inc.

I will say that what changed was clinical response.
Not just an interesting response in one patient, but also
unequivocal clinical responders in clinical trials by
RECIST, by whatever measure you employ. That
opened the door, because you cannot have a biomarker
or a mechanism until you have more than one interesting
responder in your trial. The clinical data brought people
to the field, brought the ability to understand response
and nonresponse, and everything else has followed.
Dr. Merghoub: I second what Lisa just said. Before
immunotherapy was hip, I was also doing some work on
vaccines. And it is true that we were in the back room
and nobody recognized it as something. I think it was
considered as being just an academic exercise and not
something that would translate into a real therapeutic
modality or intervention at some point.
The clinical result is what brought the community to
the realization that harnessing the immune system to
treat cancer is a viable reality. Of course, checkpoint is
not the answer to everything. It was some of the triggers to the interest in the field and of course, targeted
therapies remain a key and important therapeutic approach. Now, half of AACR is presenting on that,
which means that half the people who do research are
doing immune therapy. Even people who said to me,
''Taha, I never believed in this, but I guess you are
right. We need to work on this.''
Dr. Daver: I would say the same. For most tumors, there
is a way to harness the immune system. The future will be
a combination of immunotherapy and targeted therapies.
I think these are both extremely potent, extremely valuable. And the big thing that we are hoping is, can we get
rid, or at least minimize chemotherapy and radiation? I
think it can happen in 5 to 10 years and is already happening in trials in certain solid and heme malignancies.
Dr. Heath: I just want to add one final thing. You know,
sometimes when you are sitting in the middle of this, it
looks like progress is not as fast as you want. It is kind of
like rowing a boat across a lake. If you look behind you, it
is like, ''Whoa, look how far we have come.'' And we
have come an amazing distance in the last many years.
And then there was a big baseline for that, with people
trying to work to try to make breakthroughs that have
begun paying off. So, I think the outlook on the future is
actually very bright. I think it is remarkably encouraging.

AUTHOR DISCLOSURE
Dr. Heath is a cofounder and board member at
IsoPlexis. Dr. Butterfield does not have any competing
interests in what was discussed here, but does have a
long string of disclosures relating in general to cancer
immunotherapy that could be disclosed upon request.
No competing financial interests exist.
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