Immune Checkpoint Inhibitors: The New Breakout Stars in Cancer Treatm | Page 9
Table 4. Combination of immune checkpoint inhibitors and cytokines
IMMUNE CHECKPOINT INHIBITOR
PHASE I
NCT01629758
Nivolumab/Opdivo
CYTOKINE
IL-21
CONDITION
OTHER THERAPIES
Metastatic and/or
unresectable solid tumors
NCT02614456
IFN-gamma
Advanced solid tumors,
progressed after at least
1 treatment
NCT02112032
Pembrolizumab/MK-3475/Keytruda
pegIFN alpha-2b
Unresectable stage III/IV
melanoma
NCT02339324
IFN-alpha 2b
Advanced or recurrent
melanoma
NCT02350673
Atezolizumab/MPDL3280A
RO6895882 (IL-2
Advanced or metastatic
variant that targets
CEA-positive solid tumors
carcinoembryonic
antigen (CEA))
PHASE I/II
NCT00871481
Ipilimumab
IL-2
Recurrent or metastatic
Chemotherapy
melanoma
NCT00058279
PHASE II
NCT02027935
Ipilimumab
NCT02203604
IL-2
Melanoma
IL-2
Melanoma
IL-2
Recurrent or metastatic
Chemotherapy
melanoma
PHASE III
NCT02506153
Pembrolizumab/MK-3475/Keytruda
Recombinant IFN-
Melanoma
alpha-2b
PHASE IV
NCT01856023
Ipilimumab
immunosuppressive tumor microenvironment
consists of regulatory T cells, suppressor cells, and
NK cells, which can release soluble immunosuppressive factors such as TGF-beta, IL-10, and
VEGF.19,20 A combination approach that alters the
tumor to reduce the secreted immunosuppressive
factors using cytokines such as IL-2, IL-15, IL-7,
GM-CSF, and IFN in addition to the immunotherapy
could be useful.19,20
As such, a number of ongoing trials are exploring
the combined use of these cytokines with immune
checkpoint inhibitors (Table 4).
Vaccines
Because the blockade of checkpoints as monotherapy
might be efficacious only when there was a pre-existing
anti-tumor response in the patient, use of vaccines
to activate that response in patients without it might
amplify the response to checkpoint inhibition. As a
result, the combination might induce tumor regression
when monotherapy with either agent would not have
been successful, particularly in patients with resistance
to checkpoint inhibitors.
IL-2
Metastatic melanoma
For example, responses to PD-1 therapy likely
require the presence of CD8+ T cells in the tumor
microenvironment, and therapies such as IMCgp100
that recruit these cells to the tumor might overcome
the pre-existing resistance to checkpoint blockade.
Combination with this vaccine is currently being
studied for melanoma (NCT02535078, Table 5).
Another vaccine is being tested in a Phase II study
(NCT01096602) for acute myelogenous leukemia, in
which the leukemia stem cells that are not eradicated
during chemotherapy can support disease relapse.
The investigators of this study hypothesized that the
dendritic cell AML fusion vaccine would stimulate
the immune system to recognize the leukemia cells
as foreign, and the anti-PD-1 therapy would help to
control those cells that were resistant to chemotherapy.
Combinations of the New Stars
Immunologic checkpoints are not redundant, and the
immune functions regulated by immune checkpoints
are diverse. In addition, combination therapies are
important as cancers develop alternate pathways that do
not respond to a targeted therapy, resulting in the need
for a broad array of these targeted agents that are then
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