Clinical landscape of LAG-3-targeted therapy

Abstract

•LAG-3 is a highly important next-generation immune checkpoint molecule.•Ninety-seven clinical trials are evaluating at least 16 LAG-3-targeting molecules.•Here we identify preclinical and clinical studies conducted involving LAG-3.•Bispecific LAG-3 molecules are being developed, showing strong capacities.•LAG-3/PD-1 co-blockade is demonstrating encouraging results. Lymphocyte-activated gene 3 (LAG-3) is a cell surface inhibitory receptor and a key regulator of immune homeostasis with multiple biological activities related to T-cell functions. LAG-3 is considered a next-generation immune checkpoint of clinical importance, right next to programmed cell death protein 1 (PD-1) and cytotoxic T-cell lymphocyte antigen-4 (CTLA-4). Indeed, it is the third inhibitory receptor to be exploited in human anticancer immunotherapies. Several LAG-3-antagonistic immunotherapies are being evaluated at various stages of preclinical and clinical development. In addition, combination therapies blocking LAG-3 together with other immune checkpoints are also being evaluated at preclinical and clinical levels. Indeed, the co-blockade of LAG-3 with PD-1 is demonstrating encouraging results. A new generation of bispecific PD-1/LAG-3-blocking agents have also shown strong capacities to specifically target PD-1+ LAG-3+ highly dysfunctional T cells and enhance their proliferation and effector activities. Here we identify and classify preclinical and clinical trials conducted involving LAG-3 as a target through an extensive bibliographic research. The current understanding of LAG-3 clinical applications is summarized, and most of the publically available data up to date regarding LAG-3-targeted therapy preclinical and clinical research and development are reviewed and discussed. Lymphocyte-activated gene 3 (LAG-3) is a cell surface inhibitory receptor and a key regulator of immune homeostasis with multiple biological activities related to T-cell functions. LAG-3 is considered a next-generation immune checkpoint of clinical importance, right next to programmed cell death protein 1 (PD-1) and cytotoxic T-cell lymphocyte antigen-4 (CTLA-4). Indeed, it is the third inhibitory receptor to be exploited in human anticancer immunotherapies. Several LAG-3-antagonistic immunotherapies are being evaluated at various stages of preclinical and clinical development. In addition, combination therapies blocking LAG-3 together with other immune checkpoints are also being evaluated at preclinical and clinical levels. Indeed, the co-blockade of LAG-3 with PD-1 is demonstrating encouraging results. A new generation of bispecific PD-1/LAG-3-blocking agents have also shown strong capacities to specifically target PD-1+ LAG-3+ highly dysfunctional T cells and enhance their proliferation and effector activities. Here we identify and classify preclinical and clinical trials conducted involving LAG-3 as a target through an extensive bibliographic research. The current understanding of LAG-3 clinical applications is summarized, and most of the publically available data up to date regarding LAG-3-targeted therapy preclinical and clinical research and development are reviewed and discussed. IntroductionLymphocyte activation gene 3 (LAG-3, CD223) is a cell surface inhibitory receptor that regulates a wide range of T-cell effector functions.1Andrews L.P. Marciscano A.E. Drake C.G. Vignali D.A. LAG3 (CD223) as a cancer immunotherapy target.Immunol Rev. 2017; 276: 80-96Crossref PubMed Scopus (431) Google Scholar, 2Chocarro L. Blanco E. Zuazo M. et al.Understanding LAG-3 signaling.Int J Mol Sci. 2021; 22: 5282Crossref PubMed Scopus (25) Google Scholar, 3Huard B. Prigent P. Pages F. Bruniquel D. Triebel F. T cell major histocompatibility complex class II molecules down-regulate CD4+ T cell clone responses following LAG-3 binding.Eur J Immunol. 1996; 26: 1180-1186Crossref PubMed Scopus (96) Google Scholar, 4Huard B. Tournier M. Hercend T. Triebel F. Faure F. Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes.Eur J Immunol. 1994; 24: 3216-3221Crossref PubMed Scopus (152) Google Scholar, 5Workman C.J. Dugger K.J. Vignali D.A. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3.J Immunol. 2002; 169: 5392-5395Crossref PubMed Scopus (215) Google Scholar LAG-3 plays similar roles to other immune checkpoint molecules such as programmed cell death protein 1 (PD-1) and cytotoxic T-cell lymphocyte antigen-4 (CTLA-4). LAG-3 is expressed by T cells, some activated B cells, plasmacytoid dendritic cells (DCs) and neurons and subjected to epigenetic regulation.6Chocarro L. Blanco E. Arasanz H. et al.55P Clinical landscape of LAG-3-targeted therapy.Ann Oncol. 2021; 32: S1362Abstract Full Text Full Text PDF Google Scholar,7Saleh R. Toor S.M. Nair V.S. Elkord E. Role of epigenetic modifications in inhibitory immune checkpoints in cancer development and progression.Front Immunol. 2020; 11: 1469Crossref PubMed Scopus (30) Google Scholar In addition, LAG-3 in activated T cells delivers co-stimulatory signals to DCs, licensing them to produce interleukin-12p70 (IL-12p70).8Casati C. Camisaschi C. Novellino L. et al.Human lymphocyte activation gene-3 molecules expressed by activated T cells deliver costimulation signal dendritic cell Immunol. PubMed Scopus Google P. The and PubMed Scopus Google major histocompatibility complex and protein 1 B. R. Prigent P. et of the major histocompatibility complex class II LAG-3 PubMed Scopus Google Scholar, B. Prigent P. Tournier M. Bruniquel D. Triebel F. histocompatibility complex class II interaction with and lymphocyte activation gene-3 J Immunol. PubMed Scopus Google Scholar, T. L. et immune responses by T cells LAG-3 and of plasmacytoid dendritic PubMed Scopus Google Scholar, et protein 1 is a major immune inhibitory of Full Text Full Text PDF PubMed Scopus Google Scholar is considered the B. Prigent P. Pages F. Bruniquel D. Triebel F. T cell major histocompatibility complex class II molecules down-regulate CD4+ T cell clone responses following LAG-3 binding.Eur J Immunol. 1996; 26: 1180-1186Crossref PubMed Scopus (96) Google B. Tournier M. Hercend T. Triebel F. Faure F. Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes.Eur J Immunol. 1994; 24: 3216-3221Crossref PubMed Scopus (152) Google Scholar LAG-3 to with B. Prigent P. Tournier M. Bruniquel D. Triebel F. histocompatibility complex class II interaction with and lymphocyte activation gene-3 J Immunol. PubMed Scopus Google L. F. et immune checkpoint to cancer PubMed Scopus Google Scholar LAG-3 signal in DCs, and protein Triebel F. class II signal in human dendritic cells by a the LAG-3 protein Scopus Google Scholar with and also T-cell inhibitory by other be highly expressed cells and activated T it is T-cell and plasmacytoid T. L. et immune responses by T cells LAG-3 and of plasmacytoid dendritic PubMed Scopus Google and of cancer through interaction with PubMed Scopus Google Scholar, M. of and as of of J 2017; PubMed Google Scholar, et of by to cancer 2017; PubMed Scopus (30) Google Scholar LAG-3 to is to and to responses to 1 et protein 1 is a major immune inhibitory of Full Text Full Text PDF PubMed Scopus Google Scholar In addition, the as an LAG-3 in cells, T-cell responses by the of and F. D. et expressed cells by T-cell PubMed Scopus Google Scholar LAG-3 T-cell receptor signal by to the Tournier M. Triebel F. lymphocyte activation gene-3 molecules Immunol. Google Scholar the of negative signal are C.J. Dugger K.J. Vignali D.A. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3.J Immunol. 2002; 169: 5392-5395Crossref PubMed Scopus (215) Google Triebel F. a lymphocyte activation gene-3 protein that to a in the of in the of the activation J Immunol. PubMed Scopus Google Scholar, D. T. T. in the of the inhibitory immune LAG-3 T cell Full Text Full Text PDF PubMed Scopus Google Scholar, C.J. Vignali D.A. The LAG-3 regulates the of activated T J Immunol. PubMed Scopus Google LAG-3 is considered a T-cell to immune homeostasis in a of human L. Blanco E. Arasanz H. et al.55P Clinical landscape of LAG-3-targeted therapy.Ann Oncol. 2021; 32: S1362Abstract Full Text Full Text PDF Google Scholar LAG-3 and PD-1 in T cells is a of strong T-cell in cancer and it is with to et analysis and of and in human cell cancer and PubMed Scopus Google Scholar, T. H. L. Lymphocyte-activation gene-3 and in PubMed Scopus Google Scholar, M. Arasanz H. et is clinical responses to Mol PubMed Scopus Google Scholar, L. Zuazo M. Arasanz H. et to A 2020; 11: PubMed Scopus Google Scholar, P. et T cells are by LAG-3 and PD-1 in human PubMed Scopus Google Scholar, M. Arasanz H. et a clinical Mol 2020; PubMed Scopus Google Scholar, M. Arasanz H. et as a key to immunotherapy Immunol. 2020; 11: PubMed Scopus Google Scholar PD-1 and LAG-3 co-blockade T-cell M. Arasanz H. et is clinical responses to Mol PubMed Scopus Google P. et T cells are by LAG-3 and PD-1 in human PubMed Scopus Google et immune checkpoint protein and as immunotherapy PubMed Scopus Google Scholar, M. et LAG-3 and PD-1 to enhance T cell activation by Immunol. PubMed Scopus Google Scholar, et inhibitory receptor regulatory Full Text Full Text PDF PubMed Scopus Google Scholar Several immunotherapies LAG-3 are at various stages of clinical L. Blanco E. 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D. et A of a bispecific LAG-3 and in with cancer and to 2020; P. et of an bispecific in with that have Oncol. PubMed Google Scholar of clinical with in with is an bispecific by that to PD-1 and blocking their inhibitory is being evaluated in clinical trials at the the of is an bispecific by their to and also PD-1 and LAG-3 and preclinical data the of to PD-1 clinical is to in is an bispecific by T-cell and of bispecific as a the of and The receptor and a human T-cell bispecific also and be with to checkpoint in is clinical at in is an bispecific by the of the of PD-1 with and and of LAG-3 with H. H. P. et bispecific 2021; PubMed Scopus Google Scholar bispecific T cells, their activation by with LAG-3+ T cells, and activities in with of and T cells, and T H. H. P. et bispecific 2021; PubMed Scopus Google Scholar A clinical is in a clinical development with to the bispecific a clinical of human human with an 1 human to a PD-1 human is a PD-1 and LAG-3 checkpoint specifically highly dysfunctional LAG-3+ PD-1+ T M. Arasanz H. et is clinical responses to Mol PubMed Scopus Google C.J. C. et and LAG3 T cells to J 2021; Scholar to deliver in with to PD-1 In preclinical a checkpoint with the to the of T by a of and of cytotoxic T B. Arasanz H. et A bispecific checkpoint to the of T 2020; PubMed Google is of the most important next-generation immune checkpoint clinical trials are evaluating at least 16 LAG-3-targeting molecules 1 and trials have by and the other by be a major in clinical LAG-3 studies in and cancer are demonstrating encouraging results. we have the of LAG-3-targeting and have to of the trials LAG-3-antagonistic molecules with other have developed, showing capacities of LAG-3 with other is of LAG-3 with other immune checkpoint molecules is a of highly dysfunctional T cells in cancer LAG-3-targeting cancer immunotherapies have and and with In addition, LAG-3 regulates a of biological and as a cancer target are clinical and PD-1 and LAG-3 co-blockade to current immunotherapies. IntroductionLymphocyte activation gene 3 (LAG-3, CD223) is a cell surface inhibitory receptor that regulates a wide range of T-cell effector functions.1Andrews L.P. Marciscano A.E. Drake C.G. Vignali D.A. LAG3 (CD223) as a cancer immunotherapy target.Immunol Rev. 2017; 276: 80-96Crossref PubMed Scopus (431) Google Scholar, 2Chocarro L. Blanco E. Zuazo M. et al.Understanding LAG-3 signaling.Int J Mol Sci. 2021; 22: 5282Crossref PubMed Scopus (25) Google Scholar, 3Huard B. Prigent P. Pages F. Bruniquel D. Triebel F. T cell major histocompatibility complex class II molecules down-regulate CD4+ T cell clone responses following LAG-3 binding.Eur J Immunol. 1996; 26: 1180-1186Crossref PubMed Scopus (96) Google Scholar, 4Huard B. Tournier M. Hercend T. Triebel F. Faure F. Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes.Eur J Immunol. 1994; 24: 3216-3221Crossref PubMed Scopus (152) Google Scholar, 5Workman C.J. Dugger K.J. Vignali D.A. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3.J Immunol. 2002; 169: 5392-5395Crossref PubMed Scopus (215) Google Scholar LAG-3 plays similar roles to other immune checkpoint molecules such as programmed cell death protein 1 (PD-1) and cytotoxic T-cell lymphocyte antigen-4 (CTLA-4). LAG-3 is expressed by T cells, some activated B cells, plasmacytoid dendritic cells (DCs) and neurons and subjected to epigenetic regulation.6Chocarro L. Blanco E. Arasanz H. et al.55P Clinical landscape of LAG-3-targeted therapy.Ann Oncol. 2021; 32: S1362Abstract Full Text Full Text PDF Google Scholar,7Saleh R. Toor S.M. Nair V.S. Elkord E. Role of epigenetic modifications in inhibitory immune checkpoints in cancer development and progression.Front Immunol. 2020; 11: 1469Crossref PubMed Scopus (30) Google Scholar In addition, LAG-3 in activated T cells delivers co-stimulatory signals to DCs, licensing them to produce interleukin-12p70 (IL-12p70).8Casati C. Camisaschi C. Novellino L. et al.Human lymphocyte activation gene-3 molecules expressed by activated T cells deliver costimulation signal dendritic cell Immunol. PubMed Scopus Google P. The and PubMed Scopus Google major histocompatibility complex and protein 1 B. R. Prigent P. et of the major histocompatibility complex class II LAG-3 PubMed Scopus Google Scholar, B. Prigent P. Tournier M. Bruniquel D. Triebel F. histocompatibility complex class II interaction with and lymphocyte activation gene-3 J Immunol. PubMed Scopus Google Scholar, T. L. et immune responses by T cells LAG-3 and of plasmacytoid dendritic PubMed Scopus Google Scholar, et protein 1 is a major immune inhibitory of Full Text Full Text PDF PubMed Scopus Google Scholar is considered the B. Prigent P. Pages F. Bruniquel D. Triebel F. T cell major histocompatibility complex class II molecules down-regulate CD4+ T cell clone responses following LAG-3 binding.Eur J Immunol. 1996; 26: 1180-1186Crossref PubMed Scopus (96) Google B. Tournier M. Hercend T. Triebel F. Faure F. Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes.Eur J Immunol. 1994; 24: 3216-3221Crossref PubMed Scopus (152) Google Scholar LAG-3 to with B. Prigent P. Tournier M. Bruniquel D. Triebel F. histocompatibility complex class II interaction with and lymphocyte activation gene-3 J Immunol. PubMed Scopus Google L. F. et immune checkpoint to cancer PubMed Scopus Google Scholar LAG-3 signal in DCs, and protein Triebel F. class II signal in human dendritic cells by a the LAG-3 protein Scopus Google Scholar with and also T-cell inhibitory by other be highly expressed cells and activated T it is T-cell and plasmacytoid T. L. et immune responses by T cells LAG-3 and of plasmacytoid dendritic PubMed Scopus Google and of cancer through interaction with PubMed Scopus Google Scholar, M. of and as of of J 2017; PubMed Google Scholar, et of by to cancer 2017; PubMed Scopus (30) Google Scholar LAG-3 to is to and to responses to 1 et protein 1 is a major immune inhibitory of Full Text Full Text PDF PubMed Scopus Google Scholar In addition, the as an LAG-3 in cells, T-cell responses by the of and F. D. et expressed cells by T-cell PubMed Scopus Google Scholar LAG-3 T-cell receptor signal by to the Tournier M. Triebel F. lymphocyte activation gene-3 molecules Immunol. Google Scholar the of negative signal are C.J. Dugger K.J. Vignali D.A. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3.J Immunol. 2002; 169: 5392-5395Crossref PubMed Scopus (215) Google Triebel F. a lymphocyte activation gene-3 protein that to a in the of in the of the activation J Immunol. PubMed Scopus Google Scholar, D. T. T. in the of the inhibitory immune LAG-3 T cell Full Text Full Text PDF PubMed Scopus Google Scholar, C.J. Vignali D.A. The LAG-3 regulates the of activated T J Immunol. PubMed Scopus Google LAG-3 is considered a T-cell to immune homeostasis in a of human L. Blanco E. Arasanz H. et al.55P Clinical landscape of LAG-3-targeted therapy.Ann Oncol. 2021; 32: S1362Abstract Full Text Full Text PDF Google Scholar LAG-3 and PD-1 in T cells is a of strong T-cell in cancer and it is with to et analysis and of and in human cell cancer and PubMed Scopus Google Scholar, T. H. L. Lymphocyte-activation gene-3 and in PubMed Scopus Google Scholar, M. Arasanz H. et is clinical responses to Mol PubMed Scopus Google Scholar, L. Zuazo M. Arasanz H. et to A 2020; 11: PubMed Scopus Google Scholar, P. et T cells are by LAG-3 and PD-1 in human PubMed Scopus Google Scholar, M. Arasanz H. et a clinical Mol 2020; PubMed Scopus Google Scholar, M. Arasanz H. et as a key to immunotherapy Immunol. 2020; 11: PubMed Scopus Google Scholar PD-1 and LAG-3 co-blockade T-cell M. Arasanz H. et is clinical responses to Mol PubMed Scopus Google P. et T cells are by LAG-3 and PD-1 in human PubMed Scopus Google et immune checkpoint protein and as immunotherapy PubMed Scopus Google Scholar, M. et LAG-3 and PD-1 to enhance T cell activation by Immunol. PubMed Scopus Google Scholar, et inhibitory receptor regulatory Full Text Full Text PDF PubMed Scopus Google Scholar Several immunotherapies LAG-3 are at various stages of clinical L. Blanco E. Arasanz H. et al.55P Clinical landscape of LAG-3-targeted therapy.Ann Oncol. 2021; 32: S1362Abstract Full Text Full Text PDF Google Scholar we the publically available data LAG-3-targeted

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