Immune Checkpoint Inhibitors: The New Breakout Stars in Cancer Treatm | Page 13

In addition to augmenting cytotoxic CD8 T cells, the immune-stimulatory receptor 4-1BB generates immunological
memory and can modulate CD4 T cell, B cell, NK cell, monocyte, macrophage, and dendritic cell activity.12
Moreover, anti-tumor and anti-viral immunity, as well as amelioration of autoimmune disease, can occur with
4-1BB agonists. A study investigating the use of anti-4-1BB/CD137 for melanoma has recently completed, without
reported results yet (NCT00612664). However, completed studies of anti-CD137 monotherapy using a mouse
model of lymphoma showed a significant antitumor effect, potentially more potent than other second-generation
checkpoint inhibitors such as anti-OX40 and anti-GITR,14 and a mouse model of hepatocellular carcinoma reported
complete regression in 40-60% of the animals, with long-lasting effects.28 However, owing to the associated liver
inflammation, combination therapies with 4-1BB are currently being investigated, to take advantage of the relative
benefits without the associated toxicities. A recent study reported that the combination of 4-1BB activation and
PD-1 blockade resulted in the best antitumor response, with complete tumor rejection, compared with 4-1BB mAb
or PD-1 mAb alone, in a mouse model of colon adenocarcinoma.29 In addition, the combination of anti-CTLA-4
and anti-4-1BB therapies resulted in CD8 T-cell-mediated rejection of colon cancer, which was long-lasting.
Furthermore, while monotherapy resulted in inflammation and manifestations of autoimmunity, combination
therapy reduced autoimmunity.30
CDX-1127, an anti-CD27 drug, is currently being investigated in a Phase I study (NCT01460134) for the treatment
of CD27-expressing B-cell malignancies, any T-cell malignancy, and solid tumors. In addition, the maximum
tolerated dose and overall safety and tolerability of APX005M, an anti-CD40 agent, is currently being investigated
in a Phase I study for solid tumors (NCT02482168), and HCD122/lucatumumab, also an anti-CD40 agent, is
being tested in a Phase I trial for follicular lymphoma (NCT01275209) and has completed testing for multiple
myeloma (NCT00231166) and non-Hodgkin’s or Hodgkin’s lymphoma that underwent at least two prior therapies
(NCT00670592), but without published results as of yet. Studies have also been completed for SGN-40 (also antiCD40) for diffuse large B-cell lymphoma (NCT00655837 and NCT00435916), multiple myeloma (NCT00525447
and NCT00079716), lymphocytic leukemia (NCT00283101), and non-Hodgkin’s lymphoma (NCT00103779). A
first-in-human study for the anti-CD40 antibody ADC-1013 is currently ongoing for advanced solid tumors, by
administering it via repeated injections into the tumor tissue (NCT02379741). Results from these trials should
provide us a better understanding of the efficacy of CD-40 as monotherapy in this wide range of cancers.

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Results from these trials should provide us a
better understanding of the efficacy of CD-40
as monotherapy in this wide range of cancers.
For metastatic breast, lung, or liver cancer, MEDI6469, an anti-OX40 agent, is being investigated in a Phase I/II
study, in combination with stereotactic body radiation (NCT01862900), and MEDI0562, another anti-OX40 agent,
is being investigated in a Phase I study for advanced solid tumors (NCT02318394).
While the use of these second-generation inhibitors is being extensively investigated as monotherapy, combination
with existing and newly studied PD-1 inhibitors appears to further enhance antitumor immunity and represents the
future of these compounds (Table 7).