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LAG-3 in Cancer Immunotherapy


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LAG-3 in Cancer Immunotherapy

Cancer immunotherapy can reverse tumor immune escape by suppressing immune checkpoint pathways. It is possible that the inhibition of pathway checkpoints, including cytotoxic T lymphocyte antigen-4 (CTLA4), programmed cell death-1 (PD1) and programmed cell death ligand-1 (PDL1), could activate T cells to attack and eliminate cancer. In recent years, several trials of agents that block CTLA4, PD1 and PDL1 have demonstrated durable efficacy against renal, lung, melanoma and other cancers. In March 2015, immunotherapy reached another milestone when the FDA approved nivolumab as a second line treatment for metastatic lung squamous carcinoma. And preliminary data indicates that another important checkpoint, lymphocyte-activation gene-3 (LAG-3) may have a synergistic effect with PD1/PDL1.

LAG3 and T cell dysfunction

A member of the immunoglobulin superfamily, the LAG-3 (CD223) is a CD4-like protein, which like CD4, binds to MHC class II molecules. The gene coding for the LAG-3 protein lies adjacent to the gene coding for CD4 on human chromosome 12 and shares approximately 20% identity with the cd4 gene. LAG3 is not expressed by resting T cells but is upregulated several days after T cell activation. The known features and functions of LAG3 make it an appealing target for immune modulation, including its well-established role in the negative regulation of T cell function. For example, blockade of LAG3 in vitro augments T cell proliferation and cytokine production, and LAG3‑deficient mice have a defect in the downregulation of T cell responses induced by the superantigen staphylococcal enterotoxin B, by peptides or by Sendai virus infection.

LAG3 is upregulated on exhausted T cells compared with effector or memory T cells. Although the establishment of chronic infection by LCMV clone 13 is not altered in LAG3‑deficient mice, dual blockade of PD1 and LAG3 reverses T cell exhaustion and improves pathogen control in a synergistic manner in both LCMV clone 13 and Plasmodium falciparum infections. In the context of cancer, LAG3 is upregulated on TILs and blockade of LAG3 can enhance anti-tumour T cell responses. In addition, dual blockade of the PD1 pathway and LAG3 has been shown in mice and humans to be more effective for anti-tumour immunity than blocking either molecule alone.

LAG3 in human Tregs

In humans, the expression of LAG3 identifies a population of CD4+CD25+FoxP3+Treg in the peripheral blood. This subpopulation is expanded in the blood and at the tumor site in patients with advanced cancers. In vitro, co-culture of Treg and dendritic cells (DCs) yielded DCs with a semimature phenotype. Blocking LAG3 during the co-culture, inhibited CXCR4, CCR7 and HLA-DR upregulation and led to reduced expression of CD80, CD86, IL-6, TNF-α and IL-8 by DCs. The change in phenotype observed when blocking LAG3 suggests that LAG3 induced a partial maturation of DCs. However, maturation-associated changes triggered by LAG3 may be modulated by the engagement of other inhibitory molecules expressed by Treg. The integration of different signals delivered to DCs by Treg is likely to differ from receiving a single LAG3 signal. In vivo, LAG3 may contribute to Treg function through control of the steady-state DC migration, as Treg-conditioned DCs have been shown to trigger abortive, tolerance-inducing responses upon antigen presentation to T cells (Figure 1).

Membrane-bound LAG3 as inhibitory co-receptor: Antigen-specific T cells are activated by antigen presenting cells (APC) presenting cognate peptide.

Figure 1. Membrane-bound LAG3 as inhibitory co-receptor: Antigen-specific T cells are activated by antigen presenting cells (APC) presenting cognate peptide.

LAG3 in disease

Beyond the role it plays in a variety of autoimmune diseases, LAG3 can also reduce the body’s ability to resist infection and promote chronic infection. LAG3 prevents autoimmune disorders in the eye by inducing anterior chamber-associated immune deviation. LAG3 may regulate the functions of CD4+ and CD8+ T cells during autoimmune diabetes, and limit autoimmunity in disease-prone environments. In bone marrow transplant (BMT) patients, LAG3 can regulate CD8+ cells involved in alloreactivity, T cell proliferation and activation after BMT. In patients with chronic viral infection, the blockade of PD-1 and LAG3 could synergistically activate T cell responses and control the virus. LAG3 negatively regulates CD8+ T cells in chronic hepatitis C patients. In tuberculosis, sLAG3 is elevated both in tuberculosis patients with good prognoses and in healthy people who have been exposed to the bacteria, indicating that sLAG3 could modulate an anti-bacterial immune response in mycobacterium tuberculosis. In acquired immune deficiency, high expression of LAG3 is correlated with impaired invariant natural killer T cell cytokine production for the duration of chronic HIV-1 infection and treatment. LAG3 expression is also observed in various cancer types. Vital preclinical studies have demonstrated that LAG3 antibodies have potential for cancer immunotherapy.

Clinical trials targeting LAG3

LAG-3 may be an even more promising target in cancer immunotherapy, because anti-LAG-3 antibodies can activate T effector cells and affect Tregs function. Currently, many companies are focusing on the LAG-3 immune checkpoint in their search for novel approaches to treat malignant tumors and autoimmune disorders, many of which are now in clinical development (Table 1). On the basis of the immunomodulatory role of LAG3 on T cell function in chronic infection and cancer, the predicted mechanism of action for LAG3‑specific monoclonal antibodies is to inhibit the negative regulation of tumour-specific effector T cells. Although LAG3 biology has not been as widely studied as that of PD1, there is evidence for pleiotropic roles of LAG3 that could invoke other mechanisms of action for LAG3 blockade.

Table 1. Clinical trials with LAG-3

TypeDrugObjectivePhaseClinical trial.gov identifier
sLAG-3IMP321IMP321 given alone or with a reference flu antigenINCT00354263
sLAG-3IMP321IMP321 combined with a hepatitis B antigenINCT00354861
sLAG-3IMP321IMP321 metastatic breast carcinoma receiving first line paclitaxelINCT00349934
sLAG-3IMP321IMP321 in metastatic renal cell carcinomaINCT00351949
sLAG-3IMP321IMP321 and gemcitabine in advanced pancreatic cancerINCT00732082
sLAG-3IMP321Adjunctive IMP321 to paclitaxel in metastatic breast carcinomaIINCT02614833
Anti-LAG-3BMS-986016The safety of anti-LAG-3 alone or with anti-PD-1 in solid tumorsINCT01968109
Anti-LAG-3BMS-986016The safety of anti-LAG-3 in hematological malignant tumorsINCT02061761
Anti-LAG-3BMS-986016Anti-LAG-3 or urelumab alone or with nivolumab in recurrent glioblastomaINCT02658981
Anti-LAG-3GSK2831781GSK2831781 in healthy people and patients with plaque psoriasisINCT02195349

Summary

Cancer treatments related to CTLA-4 and PD-1/PD-L1 have achieved remarkable results. Agents targeting the PD1 pathway for cancer therapy have shown remarkable results in clinical trials, with one of the agents recently gaining FDA approval. Another important immune checkpoint, LAG-3, which is closely related to CD4, can regulate T cell proliferation, activation and homeostasis. LAG-3 plays an important role in many autoimmune diseases and promotes chronic infection and cancer. As more agents targeting molecules which negatively regulate T cell function enter clinical trials, correlative studies that address the various roles of these molecules should be carried out. Defining the predominant mechanisms of action is needed in order to develop predictive biomarkers to aid in patient selection. This knowledge will also be instrumental in designing novel combination therapies involving blockade of other inhibitory receptors or stimulation of activating receptors.

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References:

  1. Nguyen L T, Ohashi P S. Clinical blockade of PD1 and LAG3- potential mechanisms of action. Nature Reviews Immunology, 2015, 15(1):45-56.
  2. Castelli C, et al. Lymphocyte activation gene-3 (LAG-3, CD223) in plasmacytoid dendritic cells (pDCs): a molecular target for the restoration of active antitumor immunity. Oncoimmunology, 2014, 3(11).
  3. Sierro S, et al. The CD4-like molecule LAG-3, biology and therapeutic applications. Expert Opin Ther Targets, 2011, 15(1):91-101.
  4. He Y, et al. Lymphocyte‐activation gene‐3, an important immune checkpoint in cancer. Cancer Science, 2016, 107(9):1193.
  5. Camisaschi C, et al. Alternative activation of human plasmacytoid DCs in vitro and in melanoma lesions: involvement of LAG-3. Journal of Investigative Dermatology, 2014, 134(7):1893-1902.
  6. Takaya S, et al. Upregulation of Immune Checkpoint Molecules, PD-1 and LAG-3, on CD4+ and CD8+ T Cells after Gastric Cancer Surgery. Yonago Acta Medica, 2015, 58(1):39-44.

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