Simultaneous inhibition of PD-1 and LAG-3: the future of immunotherapy?

Immunotherapy has improved the prognosis of many cancers, yet a large number of patients have demonstrated resistance to current immune checkpoint inhibitors. LAG-3 is an immune checkpoint expressed on tumor-infiltrating lymphocytes CD4(+) and CD8(+), Tregs and other immune cells. Coexpression of PD-1 and LAG-3 in solid or hematological cancers is generally associated with a poor prognosis and may be responsible for immunotherapy resistance. Dual inhibition therapy in the RELATIVITY-047 trial significantly improved progression-free survival in metastatic melanoma. This article discusses the presence of a possible synergistic interaction between LAG-3 and PD-1 in the tumor microenvironment and the utility of targeting both immune checkpoint inhibitors as an effective way to bypass resistance and increase treatment efficacy. Tweetable abstractCoexpression of PD-1 and LAG-3 in solid or hematological cancers may be responsible for immunotherapy resistance; therefore, dual inhibition of PD-1 and LAG-3 may improve treatment efficacy. Plain language summaryImmunotherapy has increased survival rates for many cancer types; however, a large number of individuals experience resistance to this therapy and poor outcomes. Among the immune molecules expressed on immune cells and tumor cells, LAG-3 can favor tumor escape and progression. The coexpression of multiple immune molecules such as PD-1 and LAG-3 in multiple cancers is generally associated with a worse prognosis and might be contributing to immunotherapy failure. Dual inhibition therapy, targeting both PD-1 and LAG-3, in the RELATIVITY-047 study has shown great antitumor activity and improved survival in metastatic melanoma. This report discusses a possible synergistic interaction between LAG-3 and PD-1 within the tumor and the utility of targeting both molecules as a way to overcome resistance and improve treatment efficacy.