Expression of LAG‐3 and efficacy of combination treatment with anti‐LAG‐3 and anti‐PD‐1 monoclonal antibodies in glioblastoma

Harris-Bookman, Sarah; Mathios, Dimitrios; Martin, Allison; Xia, Yuanxuan; Kim, Eileen; Xu, Huimin; Belcaid, Zineb; Polanczyk, Magdalena J.; Barberi, Theresa J.; Theodros, Debebe; Kim, Jennifer; Taube, Janis M.; Burger, Peter C.; Selby, Mark; Taitt, Corina; Korman, Alan J.; Ye, Xiaobu; Drake, Charles G.; Brem, Henry; Pardoll, Drew M.; Lim, Michael

doi:10.1002/ijc.31661

Cited by 128 publications

(104 citation statements)

References 19 publications

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“…These successes have led to the exploration of additional inhibitory signaling pathways on immune cells. LAG-3 receptor is another inhibitory checkpoint on T cells; its potential role in cancer is supported by extensive preclinical studies (8,22,23). 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).…”

Section: Discussionmentioning

confidence: 99%

“…CD8 þ T cells coexpressing PD-1 and LAG-3 display severely impaired effector functions in a murine model of self-antigen tolerance (21), and antigen-specific T cells in human ovarian cancer are negatively regulated by PD-1 and LAG-3 (20). Multiple reports demonstrate that a large fraction of PD-1-expressing CD8 þ and CD4 þ tumor-infiltrating lymphocytes (TIL) coexpress LAG-3, supporting the dominance of PD-1 in modulating antitumor T-cell responses, as well as a direct role of LAG-3 in further suppressing the activity of a subset of PD-1expressing T cells (18,(20)(21)(22)(23)(24). Mice deficient for both PD-1 and LAG-3 show spontaneous autoimmunity and lethality, not seen in either single knockout (22,25).…”

Section: Introductionmentioning

confidence: 98%

“…Mice deficient for both PD-1 and LAG-3 show spontaneous autoimmunity and lethality, not seen in either single knockout (22,25). In addition, dual blockade of PD-1 and LAG-3 with antibodies synergistically inhibits tumor growth in preclinical tumor models (22,23,26). 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).…”

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: 98%

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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“…is regulated by inhibitory and active receptors, remarkably impact cancer immune escape [33] . Research indicated that TILs would get activated if PD-1 or LAG-3 pathway alone was blocked, either by antibodies or knocking down [34] . From a mechanistic standpoint, LAG-3 blockade is equal to the blockade of the binding between LAG-3 and HLA-II molecules.…”

Section: Cox Regression Analysis Of Rfsmentioning

confidence: 99%

“…LAG-3 has remarkable synergy with PD-1, disrupting immune responses to cancer cells [37] . According to existed research, compared with blocking either LAG-3 or PD-1 alone, blocking both pathways showed much more remarkable therapeutic e cacy for cancers [30,34] . Another study reported upregulated expression of LAG-3 in patients insensitive to PD-1 blocking treatment, thus combined strategy will improve the prognosis [29,36] .…”

Section: Cox Regression Analysis Of Rfsmentioning

confidence: 99%

LAG-3 and PD-1/PD-L1 inhibitors might become a promising treatment for small cell lung cancer

Zhang

et al. 2020

Preprint

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Background Immune therapy has achieved notable success in cancer treatment. A novel immunocheckpoint, Lymphocyte activing gene-3 (LAG-3), has shown promising therapeutic efficacy in non-small cell lung cancer (NSCLC). However, literature about LAG-3 in small cell lung cancer (SCLC) is scarce. We performed statistical analysis to explore LAG-3 expression in SCLC patients, the correlation with programmed death 1 (PD-1) and programmed death ligand 1 (PD-1), the survival predictive significance, and the possibility of becoming an immunotherapeutic checkpoint of SCLC.Methods In this study, we included 102 patients diagnosed with SCLC. The expression of protein was evaluated by immunohistochemistry (IHC) staining. We performed all the correlation analysis and survival analysis with SPSS software (version 17.0; SPSS, Inc.; Chicago, IL)Results In SCLC, none tumor cell expressed LAG-3. LAG-3-positive TILs existed in 39.2% patients. The expression of LAG-3 was remarkably associated to PD-1 and PD-L1 expression on TILs (p = 0.006, p = 0.001). LAG-3 was the only prediction for TILs PD-L1 expression (ORs = 0.161, 95% CI: 0.063–0.412, p < 0.01). Although LAG-3-positive patients had relatively longer RFS, LAG-3 expression had no statistically significant differences in predicting prognosis (p = 0.088).Conclusions LAG-3 is an important immune checkpoint closely related to PD-1/PD-L1. There was significant correlation of LAG-3, PD-1, PD-L1 expression. LAG-3 and PD-1/PD-L1 inhibitors might be a promising immune therapy for SCLC.

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A unique expression pattern of LAG3 distinct from that of other immune checkpoints in diffuse large B‐cell lymphoma

et al. 2023

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BackgroundAlthough some patients with diffuse large B‐cell lymphoma (DLBCL) show a response to immunotherapy, there are still many who do not respond. This suggests that various immune checkpoints are complicatedly intertwined in the composition of the tumor microenvironment of DLBCL.Patients and MethodsTo comprehensively understand the expression of various immune checkpoint genes in DLBCL, we performed NanoString assay in 98 patients to investigate 579 genes. In addition, we performed immunohistochemistry for LAG‐3 and PD‐L1 to compare the results with expression in NanoString assay.ResultsAs a result of hierarchical clustering of NanoString assay, 98 DLBCLs were classified into three tumor immune microenvironment clusters. Most immune checkpoint genes showed the highest expression in cluster A and the lowest in cluster C. However, the expression of LAG3 was the highest in cluster C and the lowest in cluster A, showing an expression pattern opposite to that of other immune checkpoint genes. In Cluster A, the expression of genes related to T‐cell activity such as CD8A and GZMB was increased. In Cluster C, the expression of genes related to major histocompatibility complex molecules was the highest. Immunohistochemical stains showed modest agreement with the NanoString results but did not help clustering.ConclusionOur results show that the unique expression pattern of LAG3 in DLBCL contrasts with that of other immune checkpoints. We suggest that the combination of anti‐PD‐1/PD‐L1 and anti‐LAG‐3 blockades in the immunotherapy of DLBCL patients can have a synergistic effect, improving the immunotherapy efficacy and outcome in DLBCL patients.

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Expression of LAG‐3 and efficacy of combination treatment with anti‐LAG‐3 and anti‐PD‐1 monoclonal antibodies in glioblastoma

Cited by 128 publications

References 19 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

LAG-3 and PD-1/PD-L1 inhibitors might become a promising treatment for small cell lung cancer

A unique expression pattern of LAG3 distinct from that of other immune checkpoints in diffuse large B‐cell lymphoma

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