IsoPlexis Roundtable/Literature Review - 6

EXPERT PANEL DISCUSSION
Dr. Daver: It also depends on what type of immunotherapy you are using. If you are using something that
is directed toward an antigen, like a CAR T cell or an
antibody-drug conjugate or bispecific antibody, that is
where we were seeing there is antigen escape. Basically, if you are targeting CD33 or CD19, whatever it
may be, many tumors after time then upregulate other
antigens and may escape.
But I actually like the analogy with the immune
checkpoints. It is quite different, and that is why those
who really respond actually have many years' response,
which is not something we commonly see with antibody-
drug conjugate, because with immune checkpoint inhibitors you are depending on a general enhancement of
antitumor T cells, which should then cover any type of
antigenic escape. You are continuing to educate T cells
with those kinds of antigens.
Dr. Butterfield: What I will add to what has already
been brought up is epitope spreading, and that that is
certainly an important strategy that we do not yet know
how to harness, but we have seen it as critical to outcome in vaccine studies.
We have also seen it published in adoptive cell
therapy studies, and in the patients who respond spontaneously, which is a black box. Is the tumor just ready
to allow this phenomenon of immunogenic cell death
that promotes antigen uptake in a tumor that can bring
dendritic cells to the fore, allow cross-presentation, and
the cycling of additional specificities of T cells that get
activated? This could be important to address the tumor
heterogeneity and address some of these resistance
mechanisms. Epitope spreading is an important mechanism that we do not yet know how to harness.
Dr. LeMieux: Given the complexity of the tumor
microenvironment, how does understanding the
function of different cell types involved in the immune response help accelerate the development of
novel therapies?
Dr. Merghoub: All the expressions are very related,
right? We find the relationship between the cells
within a given tissue or within a given tumor, and we
know what treatment we are giving. And you saw just
now in the discussion, somebody spoke about targeted
therapies, somebody spoke about CAR T cell therapy,
and somebody spoke about immune checkpoint. So,
depending on the context, we will be asking different
questions or probing different mechanisms.
Defining this complex relationship within the tumor
microenvironment can define why the tumor was resistant to begin with or why a tumor acquired resistance. And, it will allow us to define the next rationale
therapy that is mechanistically based that would
overcome the resistance that we have encountered.
6

Dr. Butterfield: Some of this unbiased hypothesisgenerating single-cell profiling the field has done has
made it clear that it is not just the CD8 T cell. We can
detect a pathway where NK cells have to call dendritic
cells to the tumor to allow antigen presentation and
activation of CD8 T cells.
We see roles for CD4 help, and perhaps the need to
call back NK cells for class 1 loss, and three back-toback articles a few months ago on B cell signatures, that
in vivo cross-presentation could require B cells to be
present in something approximating a tertiary lymphoid
structure that allows spreading to deal with heterogeneity. The more we look, the more cell types are important.
Dr. Heath: Right now, we are involved in a big study
on coronavirus looking at time dependence in patients,
and it is basically a crash course in immunology,
which is that you have first responders, like neutrophils
and CD8s and CD4 shepherd in, and then B cells.
And it is no surprise that we have sort of understood
CD8 T cells for a while. You can predict a lot about
them. The class 1 antigens are a little more straightforward, and the HLA diversity is a little limited. It has
been sort of a streetlamp under which I think the field
has looked for the keys.
But clearly, if you could engage B cell antibodybased immunity here, we need to understand how to do
that. We have the toolsets now to begin unraveling this
symphony of events that you really want to be able to
control, but I think we have not quite learned how to do
that yet. But of course, all these immune cell types are
important.
And as Taha said, you may want to come back and
have your first responders become important again at
different stages. Who knows? If we could control the
way the immune system sees a tumor, there are all kinds
of opportunities that we could exploit therapeutically.
Dr. Merghoub: We need to remember that this is a
dynamic process. I am remembering the heydays of
looking at PD-L1 resistance. People were looking at
these samples and determining PD-L1 expression a
year before treatment. How meaningful is that? It is
meaningless. People spoke about this as something
very static and that did not move over time. And based
at least on preclinical studies, this can change in days.
Looking in real time in each patient would be key to
tell you what are the changes that now make you respond or not respond to this next therapy you are
putting in or combining.
Dr. Daver: I think at a clinical level, just knowing this
functionality may help us select the correct therapy.
There are definitely some patients who have hot tumors, highly functional infiltrating T cells, which are
already mounting an immune infiltration response.
ª 2020 by Mary Ann Liebert, Inc.

IsoPlexis Roundtable/Literature Review

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