New Studies Show How Immunotherapies Collaborate to Treat Melanoma

New studies have uncovered how immunotherapies targeting the immune checkpoints PD1 and LAG3 work in concert to active immune responses and may improve outcomes in patients with melanoma compared with monotherapies targeting only PD1. The studies were published in Cell.

In 2022, the US Food and Drug Administration approved the LAG3-targeting drug relatlimab as a combination treatment with nivolumab, which targets PD1, for patients with metastatic melanoma. This combination therapy has been shown to be effective compared with nivolumab alone, but according to researchers, the mechanisms underlying this enhanced antitumor immunity were previously unknown. These new studies help fill this gap.

“These studies are the first in-depth interrogation of the immune system’s response to blocking PD1 and LAG3,” said Dario A. A. Vignali, PhD, chair and distinguished professor in the Department of Immunology at Pitt and senior author on 2 of the papers, via a press release. “We found that targeting PD1 versus both PD1 and LAG3 modulated the function of CD8+ T cells in surprisingly different ways. Understanding these mechanisms is relevant for how we think about combination therapies and optimizing which drugs pair best.”

For the first study, Dr. Vignali and colleagues conducted a clinical trial to investigate immune responses of melanoma patients who received relatlimab, nivolumab, or both drugs. Subsequent to assessing blood and tumor samples, they found that patients who received both drugs had enhanced CD8+ T-cell responses associated with improved cancer-killing capability compared with those from patients treated with either drug alone.

In the second study, led by Lawrence Andrews, PhD, and colleagues, the researchers used mice that had been genetically modified so that their CD8+ T cells didn’t produce PD1, LAG3, or both. In a mouse model of melanoma, the researchers showed that T cells deficient in both immune checkpoints enhanced tumor clearance and enhanced survival compared with those lacking either PD1 or LAG3.

A third study, led by the University of Pennsylvania, concurred with these observations and provided additional insights into how LAG3 and PD1 contribute to T-cell exhaustion in different ways. “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 LAG3 and PD1 alone and in combination on the immune response within these patient tumors,” said Tullia Bruno, PhD, assistant professor of immunology at Pitt. “This will give us further insight toward smart immunotherapy combinations for patients, with the hope for improved efficacy.”