LAG-3 (Lymphocyte Activation Gene 3) is a surface receptor expressed on activated T cells, an exhaustion marker with immunosuppressive activity (1). Major histocompatibility complex class II (MHC-II) is a ligand for LAG-3; additional ligands (e.g., LSECtin and galectin-3) have also been identified (1,2). Regulatory T cells (Tregs) expressing LAG-3 have enhanced suppressive activity, whereas cytotoxic CD8+ T cells expressing LAG-3 have reduced proliferation rates and effector cytokine production in cancer and autoimmune diabetes (3,4). LAG-3+ tumor-infiltrating lymphocytes (TILs) have been reported in melanoma, colon, pancreatic, breast, lung, hematopoietic, and head and neck cancer patients (5- 11), in association with aggressive clinical features. Antibody-based LAG-3 blockade in multiple cancer mouse models restores CD8+ effector T cells and diminishes Treg populations, an effect enhanced when combined with anti-PD-1 (12). Recent studies in a metastatic ovarian cancer mouse model showed that LAG-3 blockade leads to upregulation of other immune checkpoints (PD-1, CTLA4, and TIM-3), and combination therapy targeting LAG-3, PD-1, and CTLA-4 increases functional cytotoxic T cell levels while reducing Tregs and myeloidderived suppressor cells (13,14). Multiple pre-clinical and clinical studies are testing antagonistic LAG-3 agents in combination with anti-PD-1 and/or anti-CTLA4 therapy (12-15). In view of the activating properties of soluble secreted LAG-3, a soluble agonist LAG-3 antibody (IMP321) was tested in advanced solid malignancies as a single agent (15), and demonstrated sufficient tolerability and efficacy to warrant advancement to phase II (16).