Researchers may have uncovered how combination immunotherapies targeting the immune checkpoints PD-1 and LAG-3 may work together to activate immune responses in patients with melanoma, according to two recent studies published by Cillo et al and Andrews et al in Cell. The findings may shed light on why these combination therapies can improve outcomes in patients with melanoma compared with monotherapies targeting only PD-1.
Background
While combating cancer, immune checkpoints accumulate on the surface of T cells, acting like brakes on their activity and driving exhaustion. Immune checkpoint inhibitors that help release these brakes and eliminate T-cell exhaustion have revolutionized cancer treatment; however, because many patients don’t respond to treatment, more research is currently needed to understand how these drugs can be combined to improve their effectiveness.
In 2022, the LAG-3–targeting drug relatlimab was approved by the U.S. Food and Drug Administration as a combination treatment with the PD-1–targeting drug nivolumab in patients with metastatic melanoma. This combination has been shown to greatly improve patient outcomes compared with nivolumab alone. Nonetheless, the mechanisms underlying this enhanced antitumor immunity have been unknown.
Study Methods
In the recent studies, the researchers used data from a human clinical trial and animal models, to investigate responses of tumor-killing CD8-positive T cells.
“These studies are the first in-depth interrogation of the immune system’s response to blocking PD-1 and LAG-3,” explained the senior study author of both studies Dario A. A. Vignali, PhD, Chair and Distinguished Professor of the Department of Immunology at the University of Pittsburgh. “We found that targeting PD-1 vs both PD-1 and LAG-3 modulated the function of CD8-[positive] T cells in surprisingly different ways. Understanding these mechanisms is relevant for how we think about combination therapies and optimizing which drugs pair best,” he emphasized.
Findings From the First Study
In the first study, the researchers conducted a clinical trial to examine immune responses in patients with melanoma who received relatlimab, nivolumab, or a combination of both immunotherapy agents. They analyzed the patients’ blood and tumor samples and discovered that those who received the combination therapy had enhanced CD8-positive T-cell responses associated with improved cancer-killing abilities compared with those among the patients treated with either drug alone, despite the cells retaining the hallmarks of T-cell exhaustion.
“We were surprised to see that blocking both PD-1 and LAG-3 at the same time led to much greater changes than you would expect from adding the effects of blocking PD-1 or LAG-3 by themselves. These findings show that these immune checkpoints inhibit different aspects of CD8-[positive] T-cell function, which allows them to synergize in an unexpected way,” highlighted lead study author Anthony Cillo, PhD, Assistant Professor of Immunology at the University of Pittsburgh.
After assessing the patient samples, the researchers found that relatlimab was not inert. In the study, patients initially received 4 weeks of therapy with relatlimab alone, nivolumab alone, or in combination—allowing the researchers to examine the effect of each therapeutic regimen. Several previous studies have found that relatlimab alone may not improve antitumor immunity but was only effective when combined with nivolumab. By demonstrating how relatlimab impacts T-cell responses, the findings suggested that the therapy could be combined with other immunotherapies to improve responses.
Findings From the Second Study
In the second study, the researchers used mice that had been genetically modified so that their CD8-positive T cells didn’t produce PD-1, LAG-3, or both. In a mouse model of melanoma, T cells deficient in both immune checkpoints enhanced tumor clearance and improved survival compared with those lacking either PD-1 or LAG-3, reinforcing the clinical trial results. Further, their experiments revealed mechanisms in which PD-1 and LAG-3 synergized to hinder antitumor immunity.
A third study, published by Ngiow et al in Cell, concurred with these observations and provided additional insights into how LAG-3 and PD-1 may contribute to T-cell exhaustion in different ways.
Conclusions
Collectively, these three studies may provide mechanistic insights into how PD-1 and LAG-3 function alone and in combination and offer opportunities for further clinical development.
“We are particularly excited about this research because the analyses were performed on samples from patients who had not received prior immunotherapy, which allowed us to assess the impact of LAG-3 and PD-1 alone and in combination on the immune response within these patient tumors. This will give us further insight toward smart immunotherapy combinations for patients with the hope for improved efficacy,” concluded co–study author from the first study Tullia Bruno, PhD, Assistant Professor of Immunology at the University of Pittsburgh.
Disclosure: For full disclosures of the study authors, visit cell.com for the first study and the second study.
