The CD4-like molecule LAG-3, biology and therapeutic applications

Importance of the field: Promising immunotherapeutic agents targeting co-stimulatory pathways are currently being tested in clinical trials. One player in this array of regulatory pathways is the LAG-3/MHC class II axis. The lymphocyte activation gene-3 (LAG-3) is a negative co-stimulatory receptor that modulates T cell homeostasis, proliferation and activation. A recombinant soluble dimeric form of LAG-3 (sLAG-3-Ig, IMP321) shows adjuvant properties and enhances immunogenicity of tumor vaccines. Recent clinical trials produced encouraging results, especially when the human dimeric soluble form of LAG-3 (hLAG-3-Ig) was used in combination with chemotherapy. Areas covered in this review: The biological relevance of LAG-3 in vivo. Preclinical data demonstrating adjuvant properties, as well as the improvement of tumor immunity by sLAG-3-Ig. Recent advances in the clinical development of the therapeutic reagent IMP321, hLAG-3--Ig, for cancer treatment. What the reader will gain: This review summarizes preclinical and clinical data on the biological functions of LAG-3. Take home message: The LAG-3 inhibitory pathway is attracting attention, in the light of recent studies demonstrating its role in T cell unresponsiveness, and Treg function after chronic antigen stimulation. As a soluble recombinant dimer, the sLAG-3-Ig protein acts as an adjuvant for therapeutic induction of T cell responses, and may be beneficial to cancer patients when used in combination therapies.