Efficacy of BMS-986016, a monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3), in combination with nivolumab in pts with melanoma who progressed during prior anti–PD-1/PD-L1 therapy (mel prior IO) in all-comer and biomarker-enriched populations

Ascierto, Paolo A.; Bono, Petri; Bhatia, Shailender; Melero, Ignacio; Nyakas, Marta; Svane, I-M.; Larkin, James; Gomez‐Roca, Carlos; Schadendorf, Dirk; Dummer, R.; Marabelle, Aurélien; Höeller, Christoph; Maurer, Mark; Harbison, Christopher; Mitra, Priyam; Suryawanshi, Satyendra; Thudium, Kent; Muñoz-Couselo, Eva

doi:10.1093/annonc/mdx440.011

Cited by 134 publications

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“…Notably, analysis of mouse and human tumors suggests that coexpression of LAG-3 and PD-1 is associated with T-cell dysfunction (21,22), indicating that inducible LAG-3 expression on activated T cells could be a potential mechanism of therapeutic resistance to PD-1 checkpoint blockade (46). These findings have prompted efforts to explore using anti-LAG-3-blocking antibodies, either alone or in combination with anti-PD-1, in cancers (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it stands to reason that antagonistic anti-LAG-3 antibodies may improve efficacy in combination with anti-PD-1 therapies in the clinic (7,8,(27)(28)(29)(30). Currently, there are several LAG-3-targeting treatments in various phases of clinical development (31)(32)(33)(34). In particular, combination therapy of anti-LAG-3 (BMS-986016) plus anti-PD-1 (nivolumab) has shown promising clinical efficacy in patients with melanoma (33,34).…”

Section: Introductionmentioning

confidence: 99%

“…Currently, there are several LAG-3-targeting treatments in various phases of clinical development (31)(32)(33)(34). In particular, combination therapy of anti-LAG-3 (BMS-986016) plus anti-PD-1 (nivolumab) has shown promising clinical efficacy in patients with melanoma (33,34).…”

Section: Introductionmentioning

confidence: 99%

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Preclinical Development of the Anti-LAG-3 Antibody REGN3767: Characterization and Activity in Combination with the Anti-PD-1 Antibody Cemiplimab in Human PD-1xLAG-3–Knockin Mice

Burova

Hermann

Dai

et al. 2019

Molecular Cancer Therapeutics

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In the tumor microenvironment, multiple inhibitory checkpoint receptors can suppress T-cell function, thereby enabling tumor immune evasion. Blockade of one of these checkpoint receptors, PD-1, with therapeutic antibodies has produced positive clinical responses in various cancers; however, the efficacy of this approach can be further improved. Simultaneously targeting multiple inhibitory checkpoint receptors has emerged as a promising therapeutic strategy. Here, we report the development and characterization of REGN3767, a fully human IgG4 antibody targeting LAG-3, another inhibitory receptor on T cells. REGN3767 binds human and monkey LAG-3 with high affinity and specificity and blocks the interaction of LAG-3 with its ligand, MHC class II. In an engineered T-cell/antigenpresenting cell bioassay, REGN3767 alone, or in combina-tion with cemiplimab (REGN2810, human anti-PD-1 antibody), blocked inhibitory signaling to T cells mediated by hLAG-3/MHCII in the presence of PD-1/PD-L1. To test the in vivo activity of REGN3767 alone or in combination with cemiplimab, we generated human PD-1xLAG-3 knockin mice, in which the extracellular domains of mouse Pdcd1 and Lag3 were replaced with their human counterparts. In these humanized mice, treatment with cemiplimab and REGN3767 showed increased efficacy in a mouse tumor model and enhanced the secretion of proinflammatory cytokines by tumor-specific T cells. The favorable pharmacokinetics and toxicology of REGN3767 in nonhuman primates, together with enhancement of antitumor efficacy of anti-PD-1 antibody in preclinical tumor models, support its clinical development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Preclinical Development of the Anti-LAG-3 Antibody REGN3767: Characterization and Activity in Combination with the Anti-PD-1 Antibody Cemiplimab in Human PD-1xLAG-3–Knockin Mice

Burova

Hermann

Dai

et al. 2019

Molecular Cancer Therapeutics

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“…Our results demonstrated that LAG-3 Hi /PD-L1TCs − patients had a shorter DFS and OS than LAG-3 Lo /PD-L1TCs + patients. Increasing evidences have suggested that patients with positive expression of PD-L1 are more likely to benefit from anti-PD-1/PD-L1 therapy, and the patients with high LAG-3 expression (≥ 1% ) tend to respond to the immunotherapy [52].Therefore, we infered the LAG-3 Hi /PD-L1TCs − patients with worst prognosis might benefit from the anti-LAG-3 mAb or the combination of anti-LAG-3 and anti-PD-L1 mAb.…”

Section: Discussionmentioning

confidence: 99%

Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using Multiplex Quantitative Analysis

Guo

Yuan

et al. 2020

Preprint

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Background FGL1-LAG-3 pathway is a promising immunotherapeutic target and has synergistic effect with PD-1/PD-L1. However, the prognostic significance of FGL1-LAG-3 pathway and the correlation with PD-L1 in hepatocellular carcinoma (HCC) remain unkonwn. Method The distributions, associations, and clinical significances of LAG-3, FGL1, PD-L1 and CD8 protein expression in 143 HCC patients were assessed by multiplex immunofluorescence. Results We found FGL1 and LAG-3 densities were elevated while PD-L1 and CD8 were decreased in HCC tissues compared to adjacent normal liver tissues. High levels of FGL1 were strongly associated with high densities of LAG-3 + cells but not PD-L1. CD8 + T cells densities had positive correlation with PD-L1 levels and negative asscociation with FGL1 expression. Elevated densities of LAG-3 + cells and low levels of CD8 + T cells were correlated with poor disease outcome.Moreover,LAG-3 + cells deteriorated patient stratification based on the abundance of CD8 + T cells. Paitents with positive PD-L1 expression on tumor cells (PD-L1TC + ) tended to have a improved survival than that with negative PD-L1 expression on tumor cells (PD-L1TC - ). Futhermore, PD-L1TC - in combination with high densities of LAG-3 + cells showed the worst prognosis, and PD-L1TC + patients with low densities of LAG-3 + cells had the best prognosis. Conclusions LAG-3, FGL1, PD-L1 and CD8 have distinct tissue distribution and relationships with each other. High levels of LAG-3 + cells and CD8 + T cells represent unfavorable and favorable prognostic biomarkers for HCC respectively. Levels of LAG-3 + cells in combination with PD-L1 status on tumor cells have potential to identify patients who may benefit from immune checkpoints blockade combination strategies.

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“…IMP321, tested as a monotherapy (NCT00351949) or in combination with chemotherapy (NCT00732082 and NCT00349934) or vaccines [81], showed minimal activity in monotherapy [83] and modest activity using combination approaches [84]. Early data from the anti-LAG3 relatlimab used as simultaneous dual blockade targeting PD-1 together with LAG3 produced an objective response rate of 11% in melanoma patients progressing after anti-PD-1/PD-L1 monotherapy [85]. Translational data suggest that responses were associated with LAG3 expression in the TME, indicating that LAG3 might constitute a biomarker for patient selection.…”

Section: Lag3 Blockade In Cancer and Clinical Trials Testing Lag3 Tarmentioning

confidence: 99%

LAG3: The Biological Processes That Motivate Targeting This Immune Checkpoint Molecule in Human Cancer

Solinas

Migliori

Silva

et al. 2019

Cancers

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The programmed cell death 1 (PD-1) pathway is an important regulator of immune responses in peripheral tissues, including abnormal situations such as the tumor microenvironment. This pathway is currently the principal target for immunotherapeutic compounds designed to block immune checkpoint pathways, with these drugs improving clinical outcomes in a number of solid and hematological tumors. Medical oncology is experiencing an immune revolution that has scientists and clinicians looking at alternative, non-redundant inhibitory pathways also involved in regulating immune responses in cancer. A variety of targets have emerged for combinatorial approaches in immune checkpoint blockade. The main purpose of this narrative review is to summarize the biological role of lymphocyte activation gene 3 (LAG3), an emerging targetable inhibitory immune checkpoint molecule. We briefly discuss its role in infection, autoimmune disease and cancer, with a more detailed analysis of current data on LAG3 expression in breast cancer. Current clinical trials testing soluble LAG3 immunoglobulin and LAG3 antagonists are also presented in this work.

show abstract

Efficacy of BMS-986016, a monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3), in combination with nivolumab in pts with melanoma who progressed during prior anti–PD-1/PD-L1 therapy (mel prior IO) in all-comer and biomarker-enriched populations

Cited by 134 publications

References 0 publications

Preclinical Development of the Anti-LAG-3 Antibody REGN3767: Characterization and Activity in Combination with the Anti-PD-1 Antibody Cemiplimab in Human PD-1xLAG-3–Knockin Mice

Preclinical Development of the Anti-LAG-3 Antibody REGN3767: Characterization and Activity in Combination with the Anti-PD-1 Antibody Cemiplimab in Human PD-1xLAG-3–Knockin Mice

Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using Multiplex Quantitative Analysis

LAG3: The Biological Processes That Motivate Targeting This Immune Checkpoint Molecule in Human Cancer

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