What’s Next in Immune checkpoints: Is LAG-3 emerging as a potential combination partner with PD-1?
Lymphocyte Activation Gene 3 (LAG-3) is a cell surface molecule and expressed on activated T cells, natural killer cells, B cells, and plasmacytoid dendritic cells. Dysfunctional T cells can render the immune system unable to eliminate infections and cancer. Therapeutic targeting of the surface receptors that inhibit T cell function has begun to show remarkable success in clinical trials. LAG-3 may be a better checkpoint inhibitor target than PD-1 or CTLA-4 since antibodies to these two checkpoints only activate effector T cells, and do not inhibit Treg activity, whereas an antagonist LAG-3 antibody can both activate T effector cells and inhibit induced Treg suppressive activity.
Data showed that, co-inhibition of LAG-3 and PD-1 cured mice of established tumors that were largely resistant to single antibody treatment. Currently, many companies are trying to leverage this approach in clinical studies, targeting immune checkpoints.
BMS (Nivolumab and BMS-986016)
Bristol-Myers is leading in the space and developing anti-LAG-3 antibody BMS-986016. Study showed that, combining anti-LAG-3 therapy with nivolumab in patients refractory to PD-1/PD-L1 could help patients overcome resistance and restore T-cell function. According to the results presented in ASCO-17, Addition of BMS-986016 to nivolumab demonstrates encouraging initial efficacy in patients with melanoma whose disease progressed on/after prior anti–PD-1/PD-L1 therapy, and a safety profile similar to nivolumab monotherapy. There are multiple trials going on for various solid tumors and hematological malignancies, where BMS-986016 in combination with nivolumab is used to check the Safety, Tolerability, and Efficacy of the anti-LAG antibody.
Boehringer (BI-754091 and BI-754111)
Boehringer has started an open label, phase I dose-finding study of BI 754111 (Anti-LAG-3) in combination with BI 754091 (Anti-PD-1) in patients with advanced solid cancers and of BI-754111 monotherapy With subsequent combination with BI-754091 in patients with follicular lymphoma, and non-small cell lung cancer.
Regeneron (REGN-2810 and REGN-3767)
Regeneron is recruiting patients with advanced malignancies, for a phase 1 open-Label, dose-escalation and cohort expansion first-in-Human study of the safety, tolerability, activity and pharmacokinetics of REGN-3767 (Anti-LAG-3 mAb) administered alone or in combination with REGN-2810 (Anti-PD-1 mAb). It will consist of up to 3 sequential dose cohorts which will receive 1 of 3 ascending dose levels of study drug during dose escalation.
Novartis (LAG-525 and PDR-001)
Novartis has also started a phase I/II, open label, multicenter study of the safety and efficacy of LAG-525 (Anti-LAG-3) as single agent and in combination with PDR-001 (Anti-PD-1) to patients with advanced malignancies. The trial will characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor activity of LAG-525 as a single agent and in combination with PDR-001 to adult patients with solid tumors.
Prima Biomed also has LAG-3 molecules (IMP-701, IMP-731, IMP-321 etc) in its pipeline and is in the clinical development phase with Merck (Pembrolizumab) and Novartis. As a potentially synergistic immune pathway to PD-1, LAG-3 has been identified as an immune control point receptor that regulates T-cell function and whose co-inhibition along with the PD-1 could increase benefit for cancer patients.