A new target to boost cancer immunotherapy: LAG-3

Emerging research shows that cancer therapies such as checkpoint inhibitors can be advanced by targeting a novel protein. The protein, known as lymphocyte activation gene-3 or LAG-3, may prove particularly useful in improving patients’ responses to existing cancer treatments.

Killing cancer with checkpoint inhibitors

Checkpoint inhibitors are a cancer drug that attacks tumors indirectly. They rely on infusions of antibodies to block proteins called immune checkpoints. Specifically, they target one of three checkpoints: CTLA-4, PD-1, or PD-L1. The antibody barrier formed prevents checkpoint proteins from disabling immune cells and allows the immune cell to do what it normally does: recognize and attack threats, including tumors.

These inhibitors can treat a wide range of advanced cancers, from lymphoma, lung cancer, skin cancer and more. They can even be combined with chemotherapy, radiation and other cancer treatments. However, some patients do not respond to the treatment at all or may become resistant to it over time.

Researchers believe that discovering new protein targets could improve patients’ responses to these therapies. The target could provide a new angle to attack tumors, thereby providing a necessary boost to existing checkpoint inhibitors.

LAG-3, an experimental control point

Since the development of current checkpoint inhibitors, several new checkpoint proteins have been discovered. A previous article discussed PD-L2, a potential complement to PD-1 and PD-L1 targeting checkpoint inhibitors. Another promising alternative is lymphocyte activation gene-3 or LAG-3.

Lymphocyte activation gene-3 is a checkpoint protein found primarily on the surface of activated T cells. Several types of tumors can also express the protein, such as lungs, breasts and pancreas cancers. Despite his initial discovery in 1990the exact mechanisms of action have yet to be discovered. We do know that the receptor downregulates T cell function by binding to a selection of five other receptors. This is in stark contrast to the CTLA-4, PD-1, and PD-L2 checkpoints, which only interact with one or two partner proteins.

One known partner receptor is Class II Major Histocompatibility Complexes (MHC-II). Macrophages and other antigen-presenting cells rely on this protein to interact with and activate a subset of T cells. But when LAG-3 binds to the complex, the opposite happens; the checkpoint interrupts the activation of T cells and reduces the chemicals needed for the cell to survive and multiply. Notably, the checkpoint does not prevent the MHC II complex from binding to its normal partner receptor.

The checkpoint can also bind fibrinogen-like protein 1 (FGL1), a protein generally expressed at low levels in the liver and pancreas. There is evidence that several tumors – lung, prostate, colorectal and other cancer cells – upregulate this protein to evade immune detection. Other partner proteins include LSECTin And Galectin-3two receptors found on specific tumor cells, and with lower capacity Ɑ-synucleina receptor found on neurons in the central nervous system.

Other experimental routes

LAG-3 targeting may also be possible via another route: bispecific antibody therapy. This method is based on antibodies that can target two checkpoint proteins simultaneously. While these antibodies theoretically do the job of two inhibitors in one treatment, the hope is to do just that exceed the kill tumor of dual inhibitors, especially in cases of resistance to treatmentwhen LAG-3 checkpoints can be upregulated.

For example, bispecific antibodies can bridge PD-1 and LAG-3-expressing cells while blocking these checkpoints. When this happens, the close cell-to-cell contact can promote interactions that activate T cells. This bridging may also recruit other T cells to the site, potentially creating clusters of activated T cells.

Additionally, these antibodies can work more efficiently due to a phenomenon known as cross-arm avidity. Simply put, when a bispecific antibody attaches to one checkpoint, it delivers more antibodies to the area. This increases the chance of binding to the second checkpoint on nearby cells.

A bispecific antibody has emerged that targets PD-1 and LAG-3 encouraging response rates for patients with treatment-resistant solid tumors. The number of tumors was reduced in 34% of patients when it was given alone and in 19% when it was given in addition to anti-HER2 cancer treatment.

Another alternative approach involves soluble fusion proteins. This method develops an entirely new protein using components of LAG-3 checkpoints and immunoglobulin G antibodies. The fusion protein binds to MHC II complexes and activates antigen-presenting cells – in other words, they reverse the immunosuppressive signals sent by LAG-3 checkpoints. Although still experimental, the protein has demonstrated clinical efficacy late-stage breast cancer And advanced melanoma in combination therapies.

Looking forward

Cancer care continues to evolve, especially in the field of checkpoint inhibitor research. Each new discovery of an immune checkpoint opens up possibilities for innovative treatment combinations. LAG-3 targeting inhibitors, a recent addition to the arsenal of checkpoint inhibitors, have shown promise for patients with advanced melanoma since their approval in 2022. For now, however, treatment should be administered in addition to an anti-PD-1 targeting inhibitor. Ongoing research and clinical trials may uncover the underlying mechanisms of LAG-3 inhibitors, potentially broadening their therapeutic applications and improving outcomes for more patients in the future.

This article joins a growing series on monocancer treatments, including new immunotherapies such as CAR T therapy And checkpoint inhibitors. Find more at www.williamhaseltine.com