Two new studies reveal how immunotherapies that target the immune checkpoints PD1 and LAG3 collaborate to activate immune responses in patients. Their findings explain why treatments that combine approaches targeting both checkpoints can lead to better outcomes for melanoma patients compared to using therapies that focus solely on PD1.
Recent research featured in the latest edition of the journal Cell from the University of Pittsburgh explores how immunotherapies that focus on the immune checkpoints PD1 and LAG3 work together to stimulate immune responses. The research highlights why therapies that address both checkpoints can yield better results for melanoma patients compared to treatments that only target PD1.
By utilizing data from a human clinical trial along with animal studies, the researchers examined the behavior of CD8+ T cells that target tumors. During prolonged confrontations with cancer, immune checkpoints accumulate on T cell surfaces. This accumulation serves to inhibit their activity, leading to signs of exhaustion. Immune checkpoint inhibitors that act as a release for these brakes have transformed cancer treatment; however, since many patients remain unresponsive, further exploration is necessary to understand how these drugs can be combined for enhanced effectiveness.
“These studies provide the first thorough examination of the immune system’s reactions to blocking PD1 and LAG3,” explained Dario A. A. Vignali, Ph.D., chair and distinguished professor in the Department of Immunology at Pitt, who is a senior author on both papers. “We discovered that targeting PD1 alone compared to a joint approach with both PD1 and LAG3 influenced CD8+ T cells in surprisingly different manners. Gaining insight into these mechanisms is key to our understanding of combination therapies and how to select the most effective pair of drugs.”
In 2022, the FDA approved the LAG3-targeting treatment relatlimab to be used in conjunction with nivolumab, a PD1-targeting drug, for patients battling metastatic melanoma. This combination has significantly enhanced patient outcomes when compared to nivolumab used alone, but according to Vignali, the reasons behind this improved anti-tumor response were unclear. The new research helps clarify this issue.
In the first study, Vignali collaborated with co-senior authors John Kirkwood, M.D., a distinguished service professor of medicine and director of the Melanoma and Skin Cancer Program at UPMC Hillman Cancer Center, and Tullia Bruno, Ph.D., an assistant professor of immunology at Pitt, along with lead author Anthony Cillo, Ph.D., also an assistant professor of immunology at Pitt. The team conducted a clinical trial to assess the immune responses in melanoma patients who received either relatlimab, nivolumab, or a combination of both.
The analysis of blood and tumor samples revealed that patients who received both drugs exhibited stronger CD8+ T cell responses linked to improved tumor-killing abilities compared to those who were treated with either drug alone, even as these T cells continued to display signs of exhaustion.
“We were surprised that inhibiting both PD1 and LAG3 together resulted in much greater changes than what one might expect from simply adding the impacts of blocking PD1 or LAG3 individually,” stated Cillo. “These results indicate that these immune checkpoints suppress various functions of CD8+ T cells, allowing them to work together in an unforeseen manner.”
Moreover, the researchers discovered another important aspect when analyzing patient samples: relatlimab is not inactive on its own. This study had a unique approach as patients began with four weeks of therapy using either relatlimab alone, nivolumab alone, or both combined, enabling the examination of each treatment effect. Prior studies suggested that relatlimab alone did not enhance anti-tumor immunity unless paired with nivolumab. The latest findings indicate that the therapy could be combined with other immunotherapies to boost responses.
“We are particularly enthusiastic about this research as it involved samples from patients who had not undergone previous immunotherapy, which allowed us to evaluate the individual and combined effects of LAG3 and PD1 on the immune responses within these tumors,” stated Bruno. “This will provide deeper understanding toward strategic immunotherapy combinations for patients and the potential for improved efficacy.”
The second study, led by Lawrence Andrews, Ph.D., a senior scientist at Arcellx—who conducted this research as a scientist in Vignali’s lab—and Samuel Butler, a graduate student currently in Vignali’s lab, utilized genetically modified mice that lacked PD1, LAG3, or both proteins in their CD8+ T cells.
In a melanoma mouse model, T cells deficient in both immune checkpoints were better at clearing tumors and showed improved survival rates compared to those lacking only PD1 or LAG3. This result supports the earlier findings from clinical trials. Additionally, their experiments uncovered mechanisms through which PD1 and LAG3 work together to inhibit anti-tumor immunity.
A third study published in the same edition of Cell by researchers from the University of Pennsylvania, with Vignali as a co-author, corroborated these findings while providing further insights into how LAG3 and PD1 each contribute to T cell exhaustion in distinct manners.
Together, these three papers offer valuable insights into the mechanisms behind the functioning of PD1 and LAG3 individually and combined, highlighting promising avenues for future clinical development.
