Targeting immune checkpoints holds 'promise of more potent, refined' autoimmune therapies
Targeting immune checkpoints remains a key strategy in the development of treatments aimed at autoimmune disease and cancer, as well as for improving transplant outcomes, according to a review published in the Journal of Autoimmunity.
“In recent years, we have witnessed therapeutic advances designed to target dysfunctional or ‘wayward’ T cells with therapies ranging from targeted therapies (CTLA-4-Ig), targeted synthetic therapies (kinase inhibitors) and immunomodulatory agents (calcineurin antagonists, mTOR inhibitors), immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1 /PD-L1) and beyond,” Leonard H. Calabrese, DO, RJ Fasenmyer chair of clinical immunology at the Cleveland Clinic, told Healio Rheumatology.
“Along with an interprofessional group of experts in clinical immunology, rheumatology, oncology and transplantation, we tried to explore the centrality of T cells across this varied spectrum of disciplines,” he added. “Recognizing that the integrated immune response is optimal when effector pathways — i.e., cytokines, chemokines, effector cells and beyond — are balanced by immunoregulatory and tolerogenic forces. Collectively this allows the host to engage and eliminate danger — either of external or internal origin — without harming the host.”
In their review, Calabrese, who is also chief medical editor of Healio Rheumatology, and colleagues sought to examine the regulation of T-cell co-stimulation and co-inhibition, which, as they explain, is a key factor in the processes related to autoimmunity, transplant rejection and immune evasion in cancer. Focusing on the immunomodulation agents that regulate these unwanted over- and under-reactions, the authors noted that their use has led to symptom control and slowed progression among patients with rheumatoid arthritis, as well as reduced transplant rejection rates and prolonged survival in those with cancer.
In addition, Calabrese and colleagues analyzed the management of immune checkpoint inhibitor treatment in certain challenging patient populations, including those with preexisting autoimmune conditions and individuals who undergo transplants and develop cancer. They also examined the management of immune-related adverse events in patients receiving antitumor therapy. Lastly, the authors discussed the future of immune checkpoint inhibitors, including emerging targets currently in development, alongside recent revelations stemming from the use of new molecular techniques.
According to the authors, T-cell co-stimulation and co-inhibition “play vital roles in these diverse therapeutic areas.” As a target, immune checkpoints remain a powerful tool for developing treatments aimed at autoimmune diseases and cancers, as well as for improving transplant outcomes. In addition, Calabrese and colleagues stressed that enhanced collaboration and data sharing between various specialists across disciplines would improve understanding of the opposing treatment effects for autoimmune disease and transplant rejection, compared with cancer, on immune checkpoints. This, they wrote, could potentially lead to improved patient outcomes.
“We now tailor therapies based on where the balance of immune homeostasis is tilted,” Calabrese said. “For patients with cancer, checkpoint inhibitor therapy has been transformative for managing a growing number of malignancies by driving the balance of integrated immunity to the effector/inflammatory side. This favors a more robust antitumoral effect, but also can result in immune related adverse events, which can affect virtually every organ system.”
In a similar vein, downregulating T-cell effector function in transplantation can preserve organ grafts, but also has the potential to “tip the balance to the immunoregulatory/tolerogenic side,” leaving patients vulnerable to serious and/or opportunistic infections, he added.
“Other examples abound throughout the combined fields of clinical immunology,” Calabrese said. “The future appears bright, however, with the promise of more potent but refined therapeutics on the horizon to modulate T-cell function more precisely to enhance the benefits and minimize the risks. Clinical immunologists, rheumatologists, oncologists and transplant physicians among others desire to keep up with these advances in basic and clinical immunology so they can make the best therapeutic decisions and minimize the chances of untoward effects.”