Molecular Pathways and Mechanisms of LAG3 in Cancer Therapy

Abstract

Immunotherapy targeting coinhibitory receptors has been highly successful in treating a wide variety of malignancies; however, only a subset of patients exhibits durable responses. The first FDA-approved immunotherapeutics targeting coinhibitory receptors PD1 and CTLA4, alone or in combination, significantly improved survival but were also accompanied by substantial toxicity in combination. The third FDA-approved immune checkpoint inhibitor targets LAG3, a coinhibitory receptor expressed on activated CD4+ and CD8+ T cells, especially in settings of long-term antigenic stimulation, such as chronic viral infection or cancer. Mechanistically, LAG3 expression limits both the expansion of activated T cells and the size of the memory pool, suggesting that LAG3 may be a promising target for immunotherapy. Importantly, the mechanism(s) by which LAG3 contributes to CD8+ T-cell exhaustion may be distinct from those governed by PD1, indicating that the combination of anti-LAG3 and anti-PD1 may synergistically enhance antitumor immunity. Clinical studies evaluating the role of anti-LAG3 in combination with anti-PD1 are underway, and recent phase III trial results in metastatic melanoma demonstrate both the efficacy and safety of this combination. Further ongoing clinical trials are evaluating this combination across multiple tumor types and the adjuvant setting, with accompanying translational and biomarker-focused studies designed to elucidate the molecular pathways that lead to improved antitumor T-cell responses following dual blockade of PD1 and LAG3. Overall, LAG3 plays an important role in limiting T-cell activation and has now become part of the repertoire of combinatorial immunotherapeutics available for the treatment of metastatic melanoma.

Figure 1.. Timeline of scientific and clinical development of LAG3.

Discovery, development and clinical evaluation of LAG3 as an immunotherapeutic has taken place over the course of 30 years, beginning with the discovery of LAG3 in 1990 and appreciation of its inhibitory role on T cells in 2002. A subsequent major milestone was the discovery that LAG3 and PD1 synergistically inhibit T cell function in murine models of cancer, leading to subsequent assessment of LAG3 monoclonal and bispecific antibodies in the clinic, and culminating with FDA-approval of relatlimab plus nivolumab in treatment of patients with metastatic or unresectable melanoma by demonstration of efficacy over nivolumab monotherapy in the RELATIVITY-047 clinical trial.

Figure 2.. LAG3 ligand/receptor interactions and their antagonism with therapeutic agents alone or in combination with anti-PD1 therapies.

LAG3 interacts with several known ligands that can lead to inhibition of T cell function including MHC class II, CD4, TCR, Gal3, LSECtin and FGL1. Surface expression of LAG3 is regulated by ADAM10/17, which cleaves LAG3 from the surface releasing soluble LAG3. In contrast to LAG3 mediated regulation of T cell function, a LAG3-Ig fusion protein agonist has been generated to activate APCs via interaction with MHC class II. On T cells expressing LAG3, T cell activation, function and memory are inhibited following LAG3 ligation via intracellular signaling via an intracellular EP motif domain on LAG3. Blockade of LAG3 with relatlimab in conjunction with disruption of the PD1 axis with nivolumab, results in synergistic reactivation of T cell function. Bispecific antibodies such as FS118 or tebotelimab simultaneously block PD1/PDL1 and LAG3.