Advances in LAG3 cancer immunotherapeutics

Abstract

Cancer treatment has entered the age of immunotherapy. Immune checkpoint inhibitor (ICI) therapy has shown robust therapeutic potential in clinical practice, with significant improvements in progression-free survival (PFS) and overall survival (OS). Recently, checkpoint blockade of the lymphocyte activation gene 3 (LAG3) inhibitory receptor (IR) in combination with programmed death protein 1 (PD1) inhibition has been FDA approved in patients with advanced melanoma. This has encouraged the clinical evaluation of new LAG3-directed biologics in combination with other checkpoint inhibitors. Several of these studies are evaluating bispecific antibodies that target exhausted T (T_EX) cells expressing multiple IRs. This review discusses the current understanding of LAG3 in regulating antitumor immunity and the ongoing clinical testing of LAG3 inhibition in cancer.

Keywords: LAG3; bispecific antibody; cancer; immunotherapy.

Figure 1.

Combination immune checkpoint inhibitor (ICI) therapy using monospecific antibodies: therapeutic strategy in which multiple inhibitory receptors (IRs) are targeted by combination treatment with two or more separate ICIs, such as anti-programmed death protein 1 (anti-PD1) monoclonal antibody (mAb) and anti-LAG3 mAb. Bispecific antibodies (BsAbs) targeting IRs on immune cells: BsAbs selectively binding T cells that express multiple IRs, such as LAG3 and PD1 or CTLA4. BsABs directed at cell-to-cell interactions: BsAbs designed to bind tumor-adjacent T cells by targeting tumor-expressing ligand (e.g., PD1 ligand, PDL1) and T cell IR (e.g., LAG3) or designed to bind and stabilize dendritic cell (DC) and T cell interactions to enhance cell activation by targeting DC-expressing surface receptor (e.g., FcγR) and T cell IR (e.g., LAG3). Abbreviation: TCR, T cell receptor.

Figure 2.. Role of Lymphocyte activation gene 3 (LAG3) in the tumor microenvironment (TME).

Left: LAG3 homodimers colocalize to T cell receptor (TCR)/CD3 and inhibit downstream signaling. LAG3 function can be modulated by shedding via a disintegrin and metalloproteinase (ADAM) 10/17 to release soluble LAG3 (sLAG3). Middle: major histocompatibility complex II (MHCII) is the canonical ligand of LAG3. The glutamic acid–proline-rich (EP) motif of LAG3 causes disassociation of Lck from CD4 and CD8 coreceptors to inhibit T cell signaling. Right: FGL1 expressed on tumor cells or secreted (sFLG1) can bind LAG3 to attenuate T cell function. Abbreviation: APC, antigen-presenting cell.