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1586 Part IX Cell-Based Therapies

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in a trial of pidilizumab in FL. With the rapid growth of CBT trials reported an abscopal effect, whereby local radiation therapy in
in HM, there may soon be enough data to establish patterns of combination with CBT resulted in significant improvement in sys-
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response by computed tomography (CT) and PET imaging, which temic disease control. Combination therapy with local radiation
can be used to revise response criteria for treatment with CBT. therapy and ipilimumab in low-grade B-cell lymphomas is currently
being investigated in a phase 1 trial (NCT02254772).
Another combination strategy is dual blockade with two immune
FUTURE DIRECTIONS checkpoint-blocking antibodies to further augment antitumor
immune function. As discussed previously, T-cell activation is gov-
Beyond CTLA-4 and PD-1 erned by numerous receptors and while CTLA-4 and PD-1 are critical
actors, changes in expression of other checkpoint receptors may be
The interaction between T cells and tumor cells is complex, and sufficient to overcome single receptor blockade. The mechanism of
our understanding of the inhibitory and costimulatory receptors immune evasion for patients failing CBT is not yet well understood,
that govern T-cell response is rapidly growing. With the success of but could involve upregulation of alternative checkpoint receptors.
CTLA-4 and PD-1 blockade, there is great interest in many of the Supporting this theory, a recent study in melanoma revealed that
other checkpoint receptors that regulate T-cell activation. For some mice treated with CTLA-4 blockade and radiotherapy increased
of these receptors, mAbs have been developed and are in early stages expression of PD-L1 in an apparent escape pathway from CTLA-4
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of clinical development. Killer immunoglobulin-like receptor (KIR) blockade. Additional knowledge of the pattern and frequency of
is an inhibitory receptor found on NK cells. Similar to PD-1 and these escape pathways will be useful in planning combination therapy.
CTLA-4 on effector T cells, KIR is believed to facilitate evasion Dual therapy with PD-1 and CTLA-4 blockade has shown toler-
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from NK cell-mediated immune destruction. Phase 1 trials of the ability and clinical benefit in a phase 1 study in melanoma. Several
Anti-KIR monoclonal antibody, lirilumab (Bristol-Myers Squibb, phase 1 trials are underway in HMs including combination therapy
Princeton, NJ, USA), in MM and acute myeloid leukemia have with nivolumab and urelumab in NHL (NCT02253992) an anti-
demonstrated satisfactory tolerability and safety, 34,35 and additional Ox40L mAb and a PD-L1 inhibitor in aggressive B-cell lymphomas
studies are underway (NCT 01248455, NCT01687387). Lympho- (NCT02205333), and nivolumab plus ipilimumab or lirilumab in
cyte activation gene 3 (LAG-3), an inhibitory immune checkpoint R/R HMs (NCT01592370). Results from those studies are eagerly
receptor, is currently being targeted in a phase 1 trial in R/R HMs anticipated to chart the future course of combination CBT.
(NCT02061761). Another inhibitory receptor, CD27, is being tar- Finally, CBT could be combined with other types of immuno-
geted by the mAb varlilumab (Celldex Therapeutics, Hampton, NJ, therapies including tumor vaccines, oncolytic viral therapies, bispecific
USA) in a phase 1 trial in HMs with a documented PR in a patient antibodies, and chimeric antigen receptor T cells. While there are
with HL (NCT01460134). Multiple costimulatory receptors have very few results of this strategy at present, a murine study combining
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also been targeted and are in early trials. Urelumab (Bristol-Myers tumor vaccine and pidilizumab in MM, and early results from
Squibb, Princeton, NJ, USA), an anti-CD137 monoclonal antibody, a clinical trial in humans suggest that future efforts are worth
is under investigation in a phase I trial with rituximab in patients pursuing. 40
with R/R B-cell malignancies (NCT01775631). In addition, an anti-
Ox40L mAb is currently being studied in combination with PD-1
or CTLA-4 blockade in HMs in a phase 1 trial (NCT02205333). CONCLUSION
As our understanding of immune checkpoint blockade expands, it
is likely that additional targeted therapies will reach the clinic in the Immune checkpoint blockade therapy targeting CTLA-4 and PD-1
coming years. has shown impressive results in early trials in several types of HMs.
The dramatic response rates seen with PD-1 blockade in HL may
not be easily replicated in other HMs. However, with judicious
Concepts in Combination Therapy selection of tumor targets, of treatment setting, of combination
partner(s), with appropriate endpoint assessment, and with diligently
With early trials demonstrating safety and efficacy for CBT, and collaboratively pursued correlative studies, there is hope that
checkpoint-blocking antibodies are being combined together and CBT-based therapy may in the near future, fundamentally alter the
with other antitumor therapies including cytotoxic drugs, targeted treatment paradigm for many HMs.
therapies, radiation therapy, and other forms of immunotherapy. This
approach may lead to responses across a broader group of HMs than
is possible with single-agent therapy. REFERENCES
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