@article{7cadcc9d05274c1f83d9dd8b4464cc70,
title = "Expression of LAG-3 and efficacy of combination treatment with anti-LAG-3 and anti-PD-1 monoclonal antibodies in glioblastoma",
abstract = "Like in many tumor types, immunotherapy is currently under investigation to assess its potential efficacy in glioblastoma patients. Trials are under way to assess the efficacy of new immune checkpoint inhibitors including anti-PD-1 or CTLA4. We here investigate the expression and efficacy of a novel immune-checkpoint inhibitor, called LAG-3. We show that LAG-3 is expressed in human glioblastoma samples and in a mouse glioblastoma model we show that knock out or LAG-3 inhibition with a blocking antibody is efficacious against glioblastoma and can be used in combination with other immune checkpoint inhibitors toward complete eradication of the model glioblastoma tumors. From a mechanistic standpoint we show that LAG-3 expression is an early marker of T cell exhaustion and therefore early treatment with LAG-3 blocking antibody is more efficacious than later treatment. These data provide insight and support the design of trials that incorporate LAG-3 in the treatment of glioblastoma.",
keywords = "IFN-γ, T cell exhaustion, anti-LAG-3, anti-PD-1, glioblastoma",
author = "Sarah Harris-Bookman and Dimitrios Mathios and Martin, {Allison M.} and Yuanxuan Xia and Eileen Kim and Haiying Xu and Zineb Belcaid and Magdalena Polanczyk and Theresa Barberi and Debebe Theodros and Jennifer Kim and Taube, {Janis M.} and Burger, {Peter C.} and Mark Selby and Corina Taitt and Alan Korman and Xiaobu Ye and Drake, {Charles G.} and Henry Brem and Pardoll, {Drew M.} and Michael Lim",
note = "Funding Information: Key words: glioblastoma, anti-LAG-3, anti-PD-1, T cell exhaustion, IFN-γ Abbreviations: APC: antigen presenting cell; CTLA-4: cytotoxic T lymphocyte associated protein 4; HPF: high power field; IHC: immunohistochemistry; KO: knockout; LAG-3: lymphokine activation gene 3; LN: lymph nodes; mAbs: monoclonal antibodies; MHC: major histocompatibility complex; NTx: no treatment group; PD-1: programmed death 1; TILs: tumor infiltrating lymphocytes; WT: wild type Conflicts of Interest: JMT is a consultant for Bristol Meyers Squibb (BMS), Merck and AstraZeneca and receives research support from BMS. MS, CT and AK are employees of BMS and MS and CT own BMS stocks. CGD is a consultant for Agenus, Dendreon, Janssen, Lilly, Merck, MedImmune, Pierre Fabre, Roche/Genentech; receives research support from Aduro Biotech, BMS, Janssen; has ownership interests in Compugen, Harpoon, Kleo, Potenza, Tizona; and holds patents with BMS, AstraZeneca, MedImmune and Janssen. ML is a consultant for Agenus, BMS, Regeneron, Oncorus, Boston Biomedical, Tocagen, SQZ Biotechnologies, Stryker and Baxter and receives research support from Arbor, Agenus, Altor, BMS, Immunocellular, Celldex, Accuray and DNAtrix. All other authors declare no relevant disclosures. †S.H.-B. and D.M. contributed equally to this work DOI: 10.1002/ijc.31661 History: Received 8 Feb 2018; Accepted 30 May 2018; Online 23 Aug 2018 Correspondence to: Michael Lim M.D. Professor of Neurosurgery, Oncology and Radiation Oncology Johns Hopkins Hospital, Phipps 123, 600 N. Wolfe St. Baltimore, MD, 21287, E-mail: mlim3@jhmi.edu; Tel: +410-614-1627 Publisher Copyright: {\textcopyright} 2018 UICC",
year = "2018",
month = dec,
day = "15",
doi = "10.1002/ijc.31661",
language = "English (US)",
volume = "143",
pages = "3201--3208",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "12",
}