Immune Checkpoint Inhibitors: The New Breakout Stars in Cancer Treatm | Page 15

Combination with Other Targeted Drugs
Other targeted cancer therapies that are not traditionally
viewed as immunotherapies might also enhance the
response to tumors by forcing the tumors to upregulate
immune checkpoints that can then be targeted in
combination therapy. These targeted therapies essentially
“prime” the tumors to be sensitive to destruction by
activated T cells and include vascular endothelial growth
factor (VEGF)-VEGF receptor (VEGFR) inhibitors,
RAF inhibitors, antibodies targeted at receptor tyrosine
kinases, and epigenetic therapies.
The use of these targeted therapies as monotherapy
might result in tumor reduction initially, but resistance
can develop, with tumor regrowth.31 Therefore, the
combination with checkpoint inhibitors could be
particularly useful to prevent this recurrence.
Approximately 50% of cutaneous melanomas have an
activating mutation in the BRAF oncogene, and BRAF
inhibition increases PD-1 and PD-L1 levels.32 Based on
this action, the activity of tumor-infiltrating lymphocytes
increased, and survival was prolonged with PD-1 or
PD-L1 inhibition combined with BRAF inhibition for
the treatment of melanoma in a previous study.33
VEGF, which can be immunosuppressive, is secreted
by many tumor types; therefore, blocking VEGF can
enhance dendritic cell function and T cell activation.10
Combination of sunitinib, which is a VEGFR tyrosine
kinase inhibitor, with nivolumab in renal cell carcinoma
resulted in better outcomes than with monotherapy
with either drug.34
As with all of the other combination strategies, the
correct sequence is going to be important, and it has
been suggested that the targeted therapy should be
administered first to prime the T cell response.35
Biomarkers
One of the greatest challenges with many of the
immuno-oncology therapies is determining who will
benefit. As such, the search for appropriate and reliable
biomarkers is ongoing, not only to prospectively identify
the best candidates for a particular treatment but also to
monitor a patient’s response to the treatment.
Regarding immune checkpoint pathways, which are
primarily in the tumor microenvironment, key ligand
and receptor expression in biopsies of the tumor might

help to identify the dominant pathway(s) within that
tumor. PD-L1 in particular has been a biomarker of
interest for PD-1/PD-L1 therapy10 and is currently being
studied for diffuse large B-cell lymphomas (DLBCLs)
because the PD-L1 gene is overexpressed in DLBCL
patients (NCT01660776).
PD-L1 has been associated with poorer prognosis
in lung adenocarcinoma and renal cell carcinoma.24
Furthermore, with metastatic bladder cancer, tumors
that expressed PD-L1 had a threefold increase in the
response rates to anti-PD-L1 therapy.36 PD-L1 is found in
approximately 60-70% of NSCLC tumors; although PDL1 expression in these tumors is associated with poorer
prognosis, it is also associated with tumor reduction
in the presence of anti-PD-1 therapy (nivolumab or
pembrozilumab).31 However, its role as a prognostic
biomarker in melanoma remains controversial.
With the need to biopsy the tumor to determine the
levels, the accessibility of tissue and the variability
between tumor samples can be issues with determining
the levels of PD-L1 expression.24 Furthermore, PD-L1
levels are dynamic because it can be upregulated by local
inflammation and by the tumors not only on the tumor
cell but also within the microenvironment as well as
change with treatment. Another consideration is that,
although response rates are greater in tumors positive for
PD-L1, the clinical benefit that is observed without PDL1 expression appears to indicate that PD-L1-negative
status is not entirely appropriate for excluding patients
from therapy.
Similarly, 4-1BB expression might serve as a biomarker
for anti-4-1BB therapeutics in some tumor types, such
as ovarian cancer.37
Other studies have investigated the use of mismatch
repair deficiency as a potential biomarker of anti-PD-1
therapy, with response rates of 40% for mismatch repairdeficient tumors such as microsatellite instable colorectal
cancer versus 0% for mismatch repair-proficient
colorectal cancer.38
With certain tumors, imaging could be useful to monitor
the therapeutic response. There is a current Phase 0 trial
investigating the use of (18F) fluorodeoxyglucose (FDG)
PET/CT for imaging in patients with NSCLC starting
anti-PD-1/PD-L1 therapy (NCT02608528).
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