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Soo Park, MD
Soo Park, MD
Posted: Friday, September 13, 2024
Two recent studies published in the same issue of the journal Cell offered insights into the role of LAG-3 and PD-1 inhibition in the immune response of CD8-positive T cells in patients with advanced melanoma. The trials—conducted by Anthony Cillo, PhD, of the University of Pittsburgh, and E. John Wherry, PhD, of the University of Pennsylvania, Philadelphia, and colleagues—employed human participants and mouse models, respectively, to evaluate the impact of immunotherapy on the function of these 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,” stated Dario A. A. Vignali, PhD, of the University of Pittsburgh, in an institutional press release. “Understanding these mechanisms is relevant for how we think about combination therapies and optimizing which drugs pair best.”
Dr. Cillo’s study enrolled patients with advanced melanoma to receive the anti–LAG-3 therapy relatlimab-rmbw, the PD-1 inhibitor nivolumab, or both agents to evaluate their immune response to each treatment option. Biospecimen analysis from patient samples suggested the combination therapy of relatlimab plus nivolumab altered CD8-positive T-cell differentiation, as well as enhanced capacity for CD8-positive T-cell receptor signaling. Consequently, this led to increased cytotoxicity without changing the exhaustion profile of these cells. Further, the intratumoral CD8-positive T-cell signature among participants on combination therapy appeared to correlate with a favorable prognosis, the investigators indicated.
Adding to these results, Dr. Wherry’s study evaluated how the loss of LAG-3– and/or PD-1–induced molecular changes within exhausted CD8 T cells during chronic infection in a mouse model. The results of this study concluded that PD-1 and LAG-3 both play crucial roles in regulating exhausted CD8 T-cell proliferation and effector functions, respectively.
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