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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalInternational Journal of Cancer
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Glioblastoma
Monoclonal Antibodies
Blocking Antibodies
Immunotherapy
Neoplasms
Therapeutics
T-Lymphocytes

Keywords

  • anti-LAG-3
  • anti-PD-1
  • glioblastoma
  • IFN-γ
  • T cell exhaustion

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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, Haiying; Belcaid, Zineb; Polanczyk, Magdalena; Barberi, Theresa; Theodros, Debebe; Kim, Jennifer; Taube, Janis M; Burger, Peter C.; Selby, Mark; Taitt, Corina; Korman, Alan; Ye, Xiaobu; Drake, Charles G.; Brem, Henry; Pardoll, Andrew Mark; Lim, Michael.

In: International Journal of Cancer, 01.01.2018.

Research output: Contribution to journalArticle

Harris-Bookman, Sarah ; Mathios, Dimitrios ; Martin, Allison ; Xia, Yuanxuan ; Kim, Eileen ; Xu, Haiying ; Belcaid, Zineb ; Polanczyk, Magdalena ; Barberi, Theresa ; Theodros, Debebe ; Kim, Jennifer ; Taube, Janis M ; Burger, Peter C. ; Selby, Mark ; Taitt, Corina ; Korman, Alan ; Ye, Xiaobu ; Drake, Charles G. ; Brem, Henry ; Pardoll, Andrew Mark ; Lim, Michael. / Expression of LAG-3 and efficacy of combination treatment with anti-LAG-3 and anti-PD-1 monoclonal antibodies in glioblastoma. In: International Journal of Cancer. 2018.
@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 = "anti-LAG-3, anti-PD-1, glioblastoma, IFN-γ, T cell exhaustion",
author = "Sarah Harris-Bookman and Dimitrios Mathios and Allison Martin 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, {Andrew Mark} and Michael Lim",
year = "2018",
month = "1",
day = "1",
doi = "10.1002/ijc.31661",
language = "English (US)",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",

}

TY - JOUR

T1 - Expression of LAG-3 and efficacy of combination treatment with anti-LAG-3 and anti-PD-1 monoclonal antibodies in glioblastoma

AU - Harris-Bookman, Sarah

AU - Mathios, Dimitrios

AU - Martin, Allison

AU - Xia, Yuanxuan

AU - Kim, Eileen

AU - Xu, Haiying

AU - Belcaid, Zineb

AU - Polanczyk, Magdalena

AU - Barberi, Theresa

AU - Theodros, Debebe

AU - Kim, Jennifer

AU - Taube, Janis M

AU - Burger, Peter C.

AU - Selby, Mark

AU - Taitt, Corina

AU - Korman, Alan

AU - Ye, Xiaobu

AU - Drake, Charles G.

AU - Brem, Henry

AU - Pardoll, Andrew Mark

AU - Lim, Michael

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - anti-LAG-3

KW - anti-PD-1

KW - glioblastoma

KW - IFN-γ

KW - T cell exhaustion

UR - http://www.scopus.com/inward/record.url?scp=85054038380&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054038380&partnerID=8YFLogxK

U2 - 10.1002/ijc.31661

DO - 10.1002/ijc.31661

M3 - Article

C2 - 30248181

AN - SCOPUS:85054038380

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

ER -