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J Med Oncl Ther 2017 | Volume 2 Issue 3
Breast Cancer
November 01-02, 2017 | Toronto, Canada
7
th
World Congress on
T
herapies targeting T cell immune checkpoints such as
CTLA4 and PD1/PDL1 axis have shown considerable
promise in the therapy of human cancer. Combination
therapy with dual immune checkpoint blockade (ICB) was
recently shown to be highly active in melanoma. While
signaling via both PD1 and CTLA4 is known to converge
downstream and dampen T cell function, data comparing
in
vivo
effects of blockade of these immune checkpoints either
alone or in combination
in vivo
in humans are limited. Here
we have analyzed paired pre/post therapy samples from
patients treated either anti-CTLA4 (n = 5) or anti-PD1 (n = 6)
alone, or a combination of anti-CTLA4 and anti-PD1 (n = 8),
using several methodologies including multi-parameter flow
cytometry, single-cell mass-cytometry (CyTOF), Luminex
and analysis of transcriptome of purified immune cells with
exon-level arrays. We show that blockade of CTLA4, PD1
or combination blockade leads to distinct immunologic,
genomic and cytokine signatures
in vivo
. CTLA4 blockade
leads to a prominent proliferation signature
in vivo
, manifest
as an increase in Ki-67 expression in a subset of T cells with
transitional memory phenotype. PD1 blockade does not
induce this phenotype and instead leads to marked changes
in T cells expressing NK and cytolysis associated genes, as
exemplified by Granzyme+ T cells. Combination blockade
leads to non-overlapping changes in gene expression
including proliferation-associated and chemokine genes and
leads to an increase in both Ki67+and Granzyme+ T cells.
Overall, therapy-induced changes are more prominent in T
cells than in monocytes include also involve non-overlapping
changes in several alternatively spliced transcripts and non-
coding RNAs. Each of the ICB therapies also leads to a distinct
cytokine profile with differential effects on systemic levels
of sIL2R and IL1a. Changes seen in the peripheral blood T
cells can also be seen in the tumor infiltrating lymphocytes.
Combination therapy leads to an increase in interferon-
gamma producing T cells in both circulation as well as
tumor bed. PD1 expression is higher on tumor infiltrating T
cells when compared to T cells in circulation. Importantly,
PD1 receptor occupancy following anti-PD1 therapy may
be incomplete in the tumor infiltrating T cells even in the
setting of complete receptor occupancy in circulating T cells.
These data demonstrate that blockade of PD1, CTLA4 alone
or in combination have distinct immunologic effects
in vivo
and each strategy serves as a unique immune-therapeutic.
Improved understanding of the
in vivo
effects of ICB is
needed for rational development of future immune-based
combinations against cancer.
Distinct immunologic changes
in vivo
following combination versus individual PD-1 or CTLA-4
checkpoint blockade in human cancer
Mutebi Henry
Joint Clinical Research Center, Uganda