JITC Review Series: Immune Checkpoints Beyond PD-1

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,

 

Ana Carrizosa Anderson, PhD    
Series Editor                 

                                               

Dario A.A. Vignali, PhD
Series Editor