Precision4Med_Nov2021_AdvancementsInPrecisionDiagnostics - 13

ADVANCEMENTS IN PRECISION DIAGNOSTICS
BIOSPECIMEN
SOLUTIONS
in combination with chemotherapies for about 50 cancers,
and thousands of clinical trials assessing T-cell modulators
are currently underway.
ICIs present unique challenges to the development of
predictive and prognostic biomarkers. ICIs target T-cell
responses, which are not simple on-off switches for an
antitumor response. Although T cells do attack tumor cells
that express certain tumor-specific antigens, multiple signals
are required for this attack, and the T cells must overcome
defenses mounted by tumor cells. Also, T cells can run
afoul of inhibitory pathways, leading to short-lived T-cell
responses and spared tumors.
ICIs could be more successful if their use were guided by
predictive biomarkers, that is, by biomarkers capable of
providing a readout on a tumor, facilitating the selection
of therapeutic agents, and tracking the evolution of the
tumor's response to therapy. Predictive biomarkers could
even indicate whether agents should be deployed singly
or in combination.
Predictive biomarker-based tests have been approved
by the FDA as clinical diagnostics for pembrolizumab.
There are, for example, clinical diagnostics for pembrolizumab
that assess tumors for PD-L1-immunohistochemistry
(PD-L1-IHC), microsatellite instability-high (MSI-H),
or tumor mutational burden-high (TMB-H). In several
instances, the clinical diagnostics were developed by
companies working in partnership with pembrolizumab's
manufacturer, Merck & Co.
Mohini Rajasagi, PhD, senior director, Oncology Translational
Science and Clinical Biomarkers, Merck & Co.,
says that her company has two patient-centric goals for
pursuing biomarkers within translational oncology: ''The
first is to select patients most likely to derive maximum
benefit from pembrolizumab and our other oncology
assets. The second fits under our umbrella of exploratory
biomarkers.
" Exploratory biomarkers, which include molecular
correlates and gene signatures, allow us to continue to
advance our understanding of the mechanism of action
for pembrolizumab and other oncology assets. Such
exploration may help identify patients that may benefit
from pembrolizumab monotherapy versus a combination
of drugs. "
Finding the sweet spot for T-cell activation
At IGM Biosciences, Immunoglobulin M (IgM)
antibodies are being engineered to realize various
therapeutic applications. For example, the company is
developing IgM antibodies that could serve as
therapeutic bispecific T-cell engagers.
At IGM Biosciences, the lead product candidate is an engineered bispecific IgM antibody called IGM-2323. Compared with bispecific IgG
antibodies, IGM-2323 may limit supraphysiologic stimulation of T cells, potentially improving safety and tolerability, and preserving and
strengthening T-cell activation.
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Precision4Med_Nov2021_AdvancementsInPrecisionDiagnostics

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