Increased efficacy of dual proinflammatory cytokine blockade on acute GVHD while maintaining GVT effects

Lam T. Khuat; Logan V. Vick; Cordelia Dunai; Craig P. Collins; Shyam K. More; Catherine T. Le; Chien Chun Steven Pai; Kevin M. Stoffel; Emanual Maverakis; Robert J. Canter; Arta M. Monjazeb; Dan L. Longo; Mehrdad Abedi; Eunju Choi; Bruce R. Blazar; Maneesh Dave; William J. Murphy

doi:10.1182/blood.2021011216

Increased efficacy of dual proinflammatory cytokine blockade on acute GVHD while maintaining GVT effects

Lam T. Khuat, Logan V. Vick, Cordelia Dunai, Craig P. Collins, Shyam K. More, Catherine T. Le, Chien Chun Steven Pai, Kevin M. Stoffel, Emanual Maverakis, Robert J. Canter, Arta M. Monjazeb, Dan L. Longo, Mehrdad Abedi, Eunju Choi, Bruce R. Blazar, Maneesh Dave, William J. Murphy

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Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a potential curative option for treating a variety of hematologic diseases, but acute and chronic graft-versus-host disease (GVHD) remain major barriers limiting efficacy. Acute gut GVHD occurs with marked increases in proinflammatory cytokines (including TNF and IL-6), which we recently demonstrated was exacerbated in obesity resulting in severe gastrointestinal pathology. Given the pleiotropic and overlapping effects of these 2 cytokines, we assessed the impact of dual TNF and IL-6R blockade on GVHD as well as graft-versus tumor (GVT) effects in different mouse GVHD models. Early administration of combined blockade resulted in greater protection and survival from acute gut GVHD compared with single blockade regimens and even development of later chronic skin GVHD. Importantly, double cytokine blockade preserved GVT effects reinforcing that GVT and GVHD can be delineated and may result in greater efficacy in allo-HSCT.

Original language	English (US)
Pages (from-to)	2583-2588
Number of pages	6
Journal	Blood
Volume	138
Issue number	24
DOIs	https://doi.org/10.1182/blood.2021011216
State	Published - Dec 16 2021

Bibliographical note

Funding Information:
This work was funded by National Institutes of Health (NIH), National Cancer Institute R01 CA214048 (W.J.M.), NIH, National Institute of Allergy and Infectious Diseases R37 AI34495, NIH, National Heart, Lung, and Blood Institute HL56067 (B.R.B.) and the UC Davis Comprehensive Cancer Center Support Grant (CCSG) (P30 CA093373). M.D. is supported by NIH, National Institute of Diabetes and Digestive and Kidney Diseases K08DK110421.

Funding Information:
The authors thank Sean Judge and Hyeongsun Moon for their expertise and insightful feedback and suggestions. They also thank Weihong Ma from the W.J.M. laboratory, and Qian Chen in the UC Davis Pathology Core for their technical expertise and help. This work was funded by National Institutes of Health (NIH), National Cancer Institute R01 CA214048 (W.J.M.), NIH, National Institute of Allergy and Infectious Diseases R37 AI34495, NIH, National Heart, Lung, and Blood Institute HL56067 (B.R.B.) and the UC Davis Comprehensive Cancer Center Support Grant (CCSG) (P30 CA093373). M.D. is supported by NIH, National Institute of Diabetes and Digestive and Kidney Diseases K08DK110421. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

Publisher Copyright:
© 2021 American Society of Hematology

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10.1182/blood.2021011216

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Khuat, L. T., Vick, L. V., Dunai, C., Collins, C. P., More, S. K., Le, C. T., Pai, C. C. S., Stoffel, K. M., Maverakis, E., Canter, R. J., Monjazeb, A. M., Longo, D. L., Abedi, M., Choi, E., Blazar, B. R., Dave, M., & Murphy, W. J. (2021). Increased efficacy of dual proinflammatory cytokine blockade on acute GVHD while maintaining GVT effects. Blood, 138(24), 2583-2588. https://doi.org/10.1182/blood.2021011216

Khuat, LT, Vick, LV, Dunai, C, Collins, CP, More, SK, Le, CT, Pai, CCS, Stoffel, KM, Maverakis, E, Canter, RJ, Monjazeb, AM, Longo, DL, Abedi, M, Choi, E, Blazar, BR, Dave, M & Murphy, WJ 2021, 'Increased efficacy of dual proinflammatory cytokine blockade on acute GVHD while maintaining GVT effects', Blood, vol. 138, no. 24, pp. 2583-2588. https://doi.org/10.1182/blood.2021011216

@article{443967b036be4303b028dcdff7d4658e,

title = "Increased efficacy of dual proinflammatory cytokine blockade on acute GVHD while maintaining GVT effects",

abstract = "Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a potential curative option for treating a variety of hematologic diseases, but acute and chronic graft-versus-host disease (GVHD) remain major barriers limiting efficacy. Acute gut GVHD occurs with marked increases in proinflammatory cytokines (including TNF and IL-6), which we recently demonstrated was exacerbated in obesity resulting in severe gastrointestinal pathology. Given the pleiotropic and overlapping effects of these 2 cytokines, we assessed the impact of dual TNF and IL-6R blockade on GVHD as well as graft-versus tumor (GVT) effects in different mouse GVHD models. Early administration of combined blockade resulted in greater protection and survival from acute gut GVHD compared with single blockade regimens and even development of later chronic skin GVHD. Importantly, double cytokine blockade preserved GVT effects reinforcing that GVT and GVHD can be delineated and may result in greater efficacy in allo-HSCT.",

author = "Khuat, {Lam T.} and Vick, {Logan V.} and Cordelia Dunai and Collins, {Craig P.} and More, {Shyam K.} and Le, {Catherine T.} and Pai, {Chien Chun Steven} and Stoffel, {Kevin M.} and Emanual Maverakis and Canter, {Robert J.} and Monjazeb, {Arta M.} and Longo, {Dan L.} and Mehrdad Abedi and Eunju Choi and Blazar, {Bruce R.} and Maneesh Dave and Murphy, {William J.}",

note = "Funding Information: This work was funded by National Institutes of Health (NIH), National Cancer Institute R01 CA214048 (W.J.M.), NIH, National Institute of Allergy and Infectious Diseases R37 AI34495, NIH, National Heart, Lung, and Blood Institute HL56067 (B.R.B.) and the UC Davis Comprehensive Cancer Center Support Grant (CCSG) (P30 CA093373). M.D. is supported by NIH, National Institute of Diabetes and Digestive and Kidney Diseases K08DK110421. Funding Information: The authors thank Sean Judge and Hyeongsun Moon for their expertise and insightful feedback and suggestions. They also thank Weihong Ma from the W.J.M. laboratory, and Qian Chen in the UC Davis Pathology Core for their technical expertise and help. This work was funded by National Institutes of Health (NIH), National Cancer Institute R01 CA214048 (W.J.M.), NIH, National Institute of Allergy and Infectious Diseases R37 AI34495, NIH, National Heart, Lung, and Blood Institute HL56067 (B.R.B.) and the UC Davis Comprehensive Cancer Center Support Grant (CCSG) (P30 CA093373). M.D. is supported by NIH, National Institute of Diabetes and Digestive and Kidney Diseases K08DK110421. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. Publisher Copyright: {\textcopyright} 2021 American Society of Hematology",

year = "2021",

month = dec,

day = "16",

doi = "10.1182/blood.2021011216",

language = "English (US)",

volume = "138",

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T1 - Increased efficacy of dual proinflammatory cytokine blockade on acute GVHD while maintaining GVT effects

AU - Khuat, Lam T.

AU - Vick, Logan V.

AU - Dunai, Cordelia

AU - Collins, Craig P.

AU - More, Shyam K.

AU - Le, Catherine T.

AU - Pai, Chien Chun Steven

AU - Stoffel, Kevin M.

AU - Maverakis, Emanual

AU - Canter, Robert J.

AU - Monjazeb, Arta M.

AU - Longo, Dan L.

AU - Abedi, Mehrdad

AU - Choi, Eunju

AU - Blazar, Bruce R.

AU - Dave, Maneesh

AU - Murphy, William J.

N1 - Funding Information: This work was funded by National Institutes of Health (NIH), National Cancer Institute R01 CA214048 (W.J.M.), NIH, National Institute of Allergy and Infectious Diseases R37 AI34495, NIH, National Heart, Lung, and Blood Institute HL56067 (B.R.B.) and the UC Davis Comprehensive Cancer Center Support Grant (CCSG) (P30 CA093373). M.D. is supported by NIH, National Institute of Diabetes and Digestive and Kidney Diseases K08DK110421. Funding Information: The authors thank Sean Judge and Hyeongsun Moon for their expertise and insightful feedback and suggestions. They also thank Weihong Ma from the W.J.M. laboratory, and Qian Chen in the UC Davis Pathology Core for their technical expertise and help. This work was funded by National Institutes of Health (NIH), National Cancer Institute R01 CA214048 (W.J.M.), NIH, National Institute of Allergy and Infectious Diseases R37 AI34495, NIH, National Heart, Lung, and Blood Institute HL56067 (B.R.B.) and the UC Davis Comprehensive Cancer Center Support Grant (CCSG) (P30 CA093373). M.D. is supported by NIH, National Institute of Diabetes and Digestive and Kidney Diseases K08DK110421. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. Publisher Copyright: © 2021 American Society of Hematology

PY - 2021/12/16

Y1 - 2021/12/16

N2 - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a potential curative option for treating a variety of hematologic diseases, but acute and chronic graft-versus-host disease (GVHD) remain major barriers limiting efficacy. Acute gut GVHD occurs with marked increases in proinflammatory cytokines (including TNF and IL-6), which we recently demonstrated was exacerbated in obesity resulting in severe gastrointestinal pathology. Given the pleiotropic and overlapping effects of these 2 cytokines, we assessed the impact of dual TNF and IL-6R blockade on GVHD as well as graft-versus tumor (GVT) effects in different mouse GVHD models. Early administration of combined blockade resulted in greater protection and survival from acute gut GVHD compared with single blockade regimens and even development of later chronic skin GVHD. Importantly, double cytokine blockade preserved GVT effects reinforcing that GVT and GVHD can be delineated and may result in greater efficacy in allo-HSCT.

AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a potential curative option for treating a variety of hematologic diseases, but acute and chronic graft-versus-host disease (GVHD) remain major barriers limiting efficacy. Acute gut GVHD occurs with marked increases in proinflammatory cytokines (including TNF and IL-6), which we recently demonstrated was exacerbated in obesity resulting in severe gastrointestinal pathology. Given the pleiotropic and overlapping effects of these 2 cytokines, we assessed the impact of dual TNF and IL-6R blockade on GVHD as well as graft-versus tumor (GVT) effects in different mouse GVHD models. Early administration of combined blockade resulted in greater protection and survival from acute gut GVHD compared with single blockade regimens and even development of later chronic skin GVHD. Importantly, double cytokine blockade preserved GVT effects reinforcing that GVT and GVHD can be delineated and may result in greater efficacy in allo-HSCT.

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Increased efficacy of dual proinflammatory cytokine blockade on acute GVHD while maintaining GVT effects

Abstract

Bibliographical note

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