Concurrent OX40 and CD30 ligand blockade abrogates the CD4-driven autoimmunity associated with CTLA4 and PD1 blockade while preserving excellent anti-CD8 tumor immunity

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@article{c1279f620d9342f089eebab5caa83c9c,
title = "Concurrent OX40 and CD30 ligand blockade abrogates the CD4-driven autoimmunity associated with CTLA4 and PD1 blockade while preserving excellent anti-CD8 tumor immunity",
abstract = "Although strategies that block FOXP3-dependent regulatory T cell function (CTLA4 blockade) and the inhibitory receptor PD1 have shown great promise in promoting antitumor immune responses in humans, their widespread implementation for cancer immunotherapy has been hampered by significant off-target autoimmune side effects that can be lethal. Our work has shown that absence of OX40 and CD30 costimulatory signals prevents CD4 T cell-driven autoimmunity in Foxp3-deficient mice, suggesting a novel way to block these side effects. In this study, we show that excellent antitumor CD8 T cell responses can be achieved in Foxp3KO mice deficient in OX40 and CD30 signals, particularly in the presence of concurrent PD1 blockade. Furthermore, excellent antitumor immune responses can also be achieved using combinations of Abs that block CTLA4, PD1, OX40, and CD30 ligands, without CD4 T cell-driven autoimmunity. By dissociating autoimmune side effects from anticancer immune responses, this potentially shifts this antitumor approach to patients with far less advanced disease.",
keywords = "Animals, Autoimmunity, CD30 Ligand, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, CTLA-4 Antigen, Forkhead Transcription Factors, Immunotherapy, Ligands, Lymphocyte Activation, Mice, Mice, Knockout, Neoplasms, Programmed Cell Death 1 Receptor, Receptors, OX40, T-Lymphocytes, Regulatory, Journal Article",
author = "Nawaf, {Maher G} and Ulvmar, {Maria H} and Withers, {David R} and McConnell, {Fiona M} and Gaspal, {Fabrina M} and Webb, {Gwilym J} and Jones, {Nick D} and Hideo Yagita and Allison, {James P} and Lane, {Peter J L}",
note = "Copyright {\textcopyright} 2017 The Authors.",
year = "2017",
month = aug,
day = "1",
doi = "10.4049/jimmunol.1700088",
language = "English",
volume = "199",
pages = "974--981",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "3",

}

RIS

TY - JOUR

T1 - Concurrent OX40 and CD30 ligand blockade abrogates the CD4-driven autoimmunity associated with CTLA4 and PD1 blockade while preserving excellent anti-CD8 tumor immunity

AU - Nawaf, Maher G

AU - Ulvmar, Maria H

AU - Withers, David R

AU - McConnell, Fiona M

AU - Gaspal, Fabrina M

AU - Webb, Gwilym J

AU - Jones, Nick D

AU - Yagita, Hideo

AU - Allison, James P

AU - Lane, Peter J L

N1 - Copyright © 2017 The Authors.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Although strategies that block FOXP3-dependent regulatory T cell function (CTLA4 blockade) and the inhibitory receptor PD1 have shown great promise in promoting antitumor immune responses in humans, their widespread implementation for cancer immunotherapy has been hampered by significant off-target autoimmune side effects that can be lethal. Our work has shown that absence of OX40 and CD30 costimulatory signals prevents CD4 T cell-driven autoimmunity in Foxp3-deficient mice, suggesting a novel way to block these side effects. In this study, we show that excellent antitumor CD8 T cell responses can be achieved in Foxp3KO mice deficient in OX40 and CD30 signals, particularly in the presence of concurrent PD1 blockade. Furthermore, excellent antitumor immune responses can also be achieved using combinations of Abs that block CTLA4, PD1, OX40, and CD30 ligands, without CD4 T cell-driven autoimmunity. By dissociating autoimmune side effects from anticancer immune responses, this potentially shifts this antitumor approach to patients with far less advanced disease.

AB - Although strategies that block FOXP3-dependent regulatory T cell function (CTLA4 blockade) and the inhibitory receptor PD1 have shown great promise in promoting antitumor immune responses in humans, their widespread implementation for cancer immunotherapy has been hampered by significant off-target autoimmune side effects that can be lethal. Our work has shown that absence of OX40 and CD30 costimulatory signals prevents CD4 T cell-driven autoimmunity in Foxp3-deficient mice, suggesting a novel way to block these side effects. In this study, we show that excellent antitumor CD8 T cell responses can be achieved in Foxp3KO mice deficient in OX40 and CD30 signals, particularly in the presence of concurrent PD1 blockade. Furthermore, excellent antitumor immune responses can also be achieved using combinations of Abs that block CTLA4, PD1, OX40, and CD30 ligands, without CD4 T cell-driven autoimmunity. By dissociating autoimmune side effects from anticancer immune responses, this potentially shifts this antitumor approach to patients with far less advanced disease.

KW - Animals

KW - Autoimmunity

KW - CD30 Ligand

KW - CD4-Positive T-Lymphocytes

KW - CD8-Positive T-Lymphocytes

KW - CTLA-4 Antigen

KW - Forkhead Transcription Factors

KW - Immunotherapy

KW - Ligands

KW - Lymphocyte Activation

KW - Mice

KW - Mice, Knockout

KW - Neoplasms

KW - Programmed Cell Death 1 Receptor

KW - Receptors, OX40

KW - T-Lymphocytes, Regulatory

KW - Journal Article

U2 - 10.4049/jimmunol.1700088

DO - 10.4049/jimmunol.1700088

M3 - Article

C2 - 28646041

VL - 199

SP - 974

EP - 981

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 3

ER -