Enhancing Anti-PD-1 Therapy: The Impact of LAG-3 Blockade on Immune Responses in Cancer Mouse Models

MK-4280 is a human monoclonal antibody that targets Lymphocyte Activation Gene-3 (LAG-3), an immune checkpoint receptor, to hinder its interaction with the Major Histocompatibility Complex (MHC) Class II. LAG-3 is often found alongside other checkpoint receptors like PD-1 on T cells, particularly those that are exhausted. These receptors are key in maintaining immune balance in healthy individuals and are implicated in various diseases, including autoimmunity, organ rejection, infections, and cancer. Studies in mice have shown that blocking both LAG-3 and PD-1 can enhance the anti-cancer response. The molecular reasons for this are not fully understood.

Preclinical studies have been conducted to explore the impact of targeting both LAG-3 and PD-1 in cancer. A rat:mouse chimera, 28G10-mG1, was used as a stand-in for MK-4280, as it can block the LAG-3:MHC Class II interaction without triggering Fc-mediated functions. As a single treatment, 28G10-mG1 showed limited anti-tumor effects across different mouse models, even though it was systemically present and engaged its target. However, when combined with an anti-PD-1 antibody, mDX400, the combination resulted in more significant tumor growth inhibition and a higher number of complete responses in a specific tumor model, MBT-2. Mice that achieved a complete response with the combination therapy were also protected against a subsequent MBT-2 challenge, indicating the development of immune memory.

Analysis of gene expression showed that mDX400 upregulated immune-related genes, particularly on days 4 in the blood and 8 in the tumor. When combined with mDX400, 28G10-mG1 further modified the expression of many genes affected by mDX400 alone and introduced unique genes not seen with single-agent therapy. The combination therapy also increased the expression of immune pathway signatures linked to the effectiveness of Keytruda.

Further analysis using RNA sequencing showed that the combination therapy enriched several immune- and cytokine-related pathways more than mDX400 alone. These findings support the idea that targeting LAG-3 can enhance the effectiveness of PD-1 inhibition. Clinical trials combining MK-4280 with anti-PD-1 therapy (pembrolizumab/Keytruda) are currently underway.