Clinical landscape of LAG-3-targeted therapy

Chocarro, Luisa; Blanco, Ester; Arasanz, Hugo; Fernández-Rubio, Leticia; Bocanegra, Ana; Echaide, Miriam; Garnica, Maider; Ramos, Pablo; Fernández-Hinojal, G.; Vera, Ruth; Kochan, Grazyna; Escors, David

doi:10.1016/j.iotech.2022.100079

Cited by 54 publications

(52 citation statements)

References 105 publications

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“…Excitingly, combination treatment with anti-LAG-3 and anti-PD-1 antibodies in mice resistant to treatment with single antibodies showed a strong anti-tumor effect in the absence of obvious evidence of autoimmunity, suggesting the possibility of clinical efficacy and safety through combination treatment with anti-LAG-3 and anti-PD-1 antibodies [ 36 ]. Clinical trials also confirm the findings, where in patients with advanced cancer and resistance to PD-(L)1 therapy, the use of an anti-LAG-3/PD-L1 bispecific antibody showed early signs of clinical efficacy with long-term disease control in patients with prior acquired resistance [ 37 ].…”

Section: Lag-3 Expressionmentioning

confidence: 71%

“…With the exception of antibody fragments, full-length bispecific antibodies with Fc-mediated immune activity show greater potential for anti-tumor immunotherapy. The combination of anti-LAG-3 and anti-PD-1 therapies, evaluated in clinical trials can significantly enhance the anti-tumor effect [ 37 ]. LAG-3 is co-expressed with PD-1 on tumor-infiltrating CD8+ T cells, and the co-blockade of PD-1 and LAG-3 by antibodies elevated CD8+ T cells proliferation and cytokine production [ 127 ].…”

Section: Anti-lag-3 Antibody-based Therapiesmentioning

confidence: 99%

“…XmAb841 is an anti-CTLA4-LAG-3 bispecific antibody with a modified Fc domain that increases the stability and long-circulating half-life of the antibody [ 37 ]. XmAb22841 targets and binds to CTLA-4 and LAG-3 expressed on T cells in the tumor microenvironment.…”

Section: Experimental Medicine Involving Lag-3 Clinical Trialsmentioning

confidence: 99%

See 2 more Smart Citations

LAG-3 as a Potent Target for Novel Anticancer Therapies of a Wide Range of Tumors

Sauer

Szlasa

Jonderko

et al. 2022

IJMS

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LAG-3 (Lymphocyte activation gene 3) protein is a checkpoint receptor that interacts with LSEC-tin, Galectin-3 and FGL1. This interaction leads to reduced production of IL-2 and IFN-γ. LAG-3 is widely expressed in different tumor types and modulates the tumor microenvironment through immunosuppressive effects. Differential expression in various tumor types influences patient prognosis, which is often associated with coexpression with immune checkpoint inhibitors, such as TIM-3, PD-1 and CTLA-4. Here, we discuss expression profiles in different tumor types. To date, many clinical trials have been conducted using LAG-3 inhibitors, which can be divided into anti-LAG-3 monoclonal antibodies, anti-LAG-3 bispecifics and soluble LAG-3-Ig fusion proteins. LAG-3 inhibitors supress T-cell proliferation and activation by disallowing for the interaction between LAG-3 to MHC-II. The process enhances anti-tumor immune response. In this paper, we will review the current state of knowledge on the structure, function and expression of LAG-3 in various types of cancer, as well as its correlation with overall prognosis, involvement in cell-based therapies and experimental medicine. We will consider the role of compounds targeting LAG-3 in clinical trials both as monotherapy and in combination, which will provide data relating to the efficacy and safety of proposed drug candidates.

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Section: Lag-3 Expressionmentioning

confidence: 71%

Section: Anti-lag-3 Antibody-based Therapiesmentioning

confidence: 99%

See 1 more Smart Citation

LAG-3 as a Potent Target for Novel Anticancer Therapies of a Wide Range of Tumors

Sauer

Szlasa

Jonderko

et al. 2022

IJMS

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“…The LAG-3 molecule has recently emerged as a promising cancer immunotherapy target and a highly important next-generation immune checkpoint molecule [ 1 , 2 , 3 ]. Closely related to CD4, and adjacent to its locus, it presents a similar genetic organization [ 4 ].…”

Section: Preclinical and Clinical Development Of Opdualagmentioning

confidence: 99%

“…LAG-3 over-expression confers resistance to PD-1 blockade. Indeed, PD-1/LAG-3 co-blockade is demonstrating encouraging results and strong capacities both in preclinical and clinical research [ 2 ]. In this context, LAG-3-targeted therapies have emerged as a cancer immunotherapy alone and in combination with anti-PD-1 treatments.…”

Section: Preclinical and Clinical Development Of Opdualagmentioning

confidence: 99%

Cutting-Edge: Preclinical and Clinical Development of the First Approved Lag-3 Inhibitor

Chocarro

Bocanegra

Blanco

et al. 2022

Cells

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Immune checkpoint inhibitors (ICIs) have revolutionized medical practice in oncology since the FDA approval of the first ICI 11 years ago. In light of this, Lymphocyte-Activation Gene 3 (LAG-3) is one of the most important next-generation immune checkpoint molecules, playing a similar role as Programmed cell Death protein 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4). 19 LAG-3 targeting molecules are being evaluated at 108 clinical trials which are demonstrating positive results, including promising bispecific molecules targeting LAG-3 simultaneously with other ICIs. Recently, a new dual anti-PD-1 (Nivolumab) and anti-LAG-3 (Relatimab) treatment developed by Bristol Myers Squibb (Opdualag), was approved by the Food and Drug Administration (FDA) as the first LAG-3 blocking antibody combination for unresectable or metastatic melanoma. This novel immunotherapy combination more than doubled median progression-free survival (PFS) when compared to nivolumab monotherapy (10.1 months versus 4.6 months). Here, we analyze the large clinical trial responsible for this historical approval (RELATIVITY-047), and discuss the preclinical and clinical developments that led to its jump into clinical practice. We will also summarize results achieved by other LAG-3 targeting molecules with promising anti-tumor activities currently under clinical development in phases I, I/II, II, and III. Opdualag will boost the entry of more LAG-3 targeting molecules into clinical practice, supporting the accumulating evidence highlighting the pivotal role of LAG-3 in cancer.

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