The following is a summary of “Molecular Pathways and Mechanisms of LAG3 in Cancer Therapy” published in the December 2022 issue of Clinical Cancer by Andrews et al.

Although immunotherapy that focuses on co-inhibitory receptors has shown great promise in treating a wide range of cancers, only a minority of patients show sustained responses. However, when used together, the first FDA-approved immunotherapies that targeted the coinhibitory receptors PD1 and CTLA4 greatly enhanced survival. LAG3 is a coinhibitory receptor expressed on activated CD4+ and CD8+ T lymphocytes, especially in the presence of long-term antigenic stimulation, such as in chronic viral infection or malignancy. 

This receptor targets the third immune checkpoint inhibitor licensed by the FDA. LAG3 is a potential immunotherapeutic target because it restricts the growth of activated T cells and the size of the memory pool. Importantly, the mechanisms by which LAG3 leads to CD8+ T-cell exhaustion may be separate from those mediated by PD1, suggesting that anti-LAG3 and anti-PD1 may synergistically boost antitumor immunity. Recent results from a phase III trial in patients with metastatic melanoma show that the combination of anti-LAG3 and anti-PD1 is effective and safe. 

Adjoining translational and biomarker-focused studies aim to elucidate the molecular pathways that lead to improved antitumor T-cell responses following the dual blockade of PD1 and LAG3. Additional ongoing clinical trials are assessing this combination across multiple tumor types and in the adjuvant setting. Overall, LAG3 is crucial in restricting T-cell activation and is now a part of the arsenal of combinatorial immunotherapeutics for treating metastatic melanoma.

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