Cure Alveolar Soft Part Sarcoma International (iCureASPS)

Abstract

The success of immunotherapy in many disease entities is limited to a specific subpopulation of patients. To overcome this problem, dual blockade treatments mainly against cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed cell death receptor (ligand) 1 (PD-(L)1) axis were developed. However, due to high toxicity rates and treatment resistance, alternative pathways and novel strategies were desperately needed. Lymphocyte-associated gene 3 (LAG3) represents an inhibitory receptor, which is mainly found on activated immune cells and involved in the exhaustion of T cells in malignant diseases. Its co-expression with other inhibitory receptors, particularly with PD-1 leads to an extensive research on the blockade of LAG3 and PD-1 in preclinical settings. Interestingly, several in-vivo approaches demonstrated a highly significant clinical benefit under dual blockade, whereas the efficacy was very low in case of single agent targeting. Moreover, human tumour tissues showed co-expression of LAG3 and PD-1 in infiltrated lymphocytes, which again generated a rationale for blocking these both molecules in clinical settings. The ongoing clinical studies mainly use dual blockage of LAG3/PD-1, which demonstrated promising survival benefits and long duration of response rates. The following review focuses on the biological background and rationale of combining LAG3 with other agents and serves as an update on the state of clinical research on LAG3 targeting.

https://esmoopen.bmj.com/content/4/2/e000482

Conclusions

Due to the success gained by the dual blockage of CTLA4 and PD-(L)1, new approaches for single immunotherapies, which might enhance their efficacy are established. In the last few years, LAG3 has gained widespread interest as an inhibitory receptor. Its synergistic biology with PD-1 provided a reasonable rationale to combine this molecule with anti-PD-1 agents. There are currently 11 molecules, which target LAG3 and are already being tested in clinical trials. The results of the early clinical trials demonstrate modest benefit of single anti-LAG3 treatment, which again supports potential combination approaches with other inhibitory receptors.

There are still many unanswered questions regarding the LAG3 biology including its exact function and the existence of ligands other than the MHC class II. Until now, LAG3 has mainly been combined with the PD-(L)1 axis in clinical trials. If a combination with other inhibitory molecules is feasible or not still remains unclear. The clinical implications of LAG3 as a biomarker is also a less reported issue. Whether circulating soluble LAG3 or tissue expression of LAG3 could be used as biomarkers in the course of immunotherapy is now one of the questions, which hopefully will be answered in large clinical trials. Nevertheless, apart from the lack of knowledge on its function and its effector cells, preliminary data, which has been demonstrated so far by phase I trials and congress reports, shows promising and durable response rates with acceptable toxicity, making this molecule a focus of intensive research.