Checkpoint blockade—therapies that disrupt the interaction between co-inhibitory receptors on T cells and their cognate ligands thereby blunting activation and proliferation despite antigen engagement—is a testament to the power of translational research. What began as a curiosity-driven inquiry into the mechanisms of immune tolerance has blossomed into a fourth pillar of cancer treatment, complementing the traditional triumvirate of chemotherapy, surgery, and radiation to provide remarkable benefits to thousands of patients.
The discovery of immune checkpoints spurred a renaissance in
immuno-oncology, with parallel efforts directed at translating known mechanisms
of T cell inhibition into clinically available therapies as well as at the
identification of additional targets.
In the past year alone, more than one dozen new approvals
were granted in the US for immunotherapies targeting the PD-1/PD-L1 axis. With
more than 3,000 active clinical trials evaluating these regimens, not
only for advanced or metastatic disease but also in the adjuvant or neoadjuvant
settings, the pace of approvals for checkpoint inhibitors is not looking to
slow down any time soon.
Despite this unprecedented advancement, a large subset of
cancer patients do not respond to PD-1/PD-L1-directed therapies. Additionally,
only one approved therapy targets an immune checkpoint other than the
PD-1/PD-L1 axis: the anti-CTLA-4 antibody ipilimumab. In recent years, it has
become apparent that a panoply of additional signaling pathways modulate T cell
activity, with distinct mechanisms outside the role of the PD-1 pathway in controlling
ongoing localized inflammatory responses or the function of CTLA-4 in systemic
self-tolerance. Some of these newly discovered checkpoints are already the
target of numerous investigational agents in human trials and widely considered
to be on the cusp of approval, as in the case of LAG-3.
Accumulated experience with the approved checkpoint
inhibitors targeting the PD-1 axis has also enabled reverse translational
studies that reveal new nuances of the immune landscape of the tumor
microenvironment. In addition to the discovery of new co-stimulatory or
co-inhibitory receptors and ligands, a prominent role for populations outside
the lymphoid lineage has come to light in the activation or suppression of T
cell responses, including the importance of innate immune cells and stromal
cells for anti-tumor activity. Several of the novel checkpoints that have been
discovered in recent years have also been demonstrated to play critical roles
in innate-mediated anti-tumor immunity—an important and ongoing area of study
for the immunotherapy field.
Translating observations from pre-clinical models into
usable therapies is not without challenges, however, and several
investigational agents targeting novel immune checkpoints have, to date,
yielded disappointing responses as monotherapies in randomized trials. Yet
ongoing studies show hints of promising synergy between existing
PD-1/PD-L1-targeting therapies and agents targeting novel checkpoints.
Intriguingly, some new agents have demonstrated activity in tumor types
generally thought to be weakly immunogenic, suggesting that expanding the
repertoire of immune checkpoints could open up new settings amenable to
immunotherapy.
Although the clinical development process for novel drugs
may seem slow, especially in light of the urgent need for effective therapies
for all-too-many still-lethal cancers, checkpoint inhibitors beyond
anti-PD-1/PD-L1 agents are poised for a breakthrough. Industry has placed large
bets on emerging checkpoints such as LAG-3, TIM-3 and TIGIT, and academia
continues to advance the research pipeline.
This review series supports the ongoing momentum for investigation
and clinical development of immune checkpoints therapies beyond the PD-1 axis. The
articles highlight all aspects of the translational research pipeline—including
pre-clinical rationale for novel targets, ongoing human studies, and high-level
considerations for trial design. Readers from across the clinical-translational
research enterprise will find value in these exceptional reviews. It is an
exciting time for immunotherapy, and, with JITC,
we are proud to move the field forward in this promising new direction.
Best Regards,
Series Editor
Dario
A.A. Vignali, PhD
Series Editor
No comments:
Post a Comment