Upregulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and patients with cancer

Ayumi Hashimoto; Debashis Sarker; Vikash Reebye; Sheba Jarvis; Mikael H. Sodergren; Andrew Kossenkov; Emilio Sanseviero; Nina Raulf; Jenni Vasara; Pinelopi Andrikakou; Tim Meyer; Kai Wen Huang; Ruth Plummer; Cheng E. Chee; Duncan Spalding; Madhava Pai; Shahid Khan; David J. Pinato; Rohini Sharma; Bristi Basu; Daniel Palmer; Yuk Ting Ma; Jeff Evans; Robert Habib; Anna Martirosyan; Naouel Elasri; Adeline Reynaud; John J. Rossi; Mark Cobbold; Nagy A. Habib; Dmitry I. Gabrilovich

doi:10.1158/1078-0432.CCR-21-0986

Upregulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and patients with cancer

Ayumi Hashimoto, Debashis Sarker, Vikash Reebye^*, Sheba Jarvis, Mikael H. Sodergren, Andrew Kossenkov, Emilio Sanseviero, Nina Raulf, Jenni Vasara, Pinelopi Andrikakou, Tim Meyer, Kai Wen Huang, Ruth Plummer, Cheng E. Chee, Duncan Spalding, Madhava Pai, Shahid Khan, David J. Pinato, Rohini Sharma, Bristi BasuDaniel Palmer, Yuk Ting Ma, Jeff Evans, Robert Habib, Anna Martirosyan, Naouel Elasri, Adeline Reynaud, John J. Rossi, Mark Cobbold, Nagy A. Habib, Dmitry I. Gabrilovich

^*Corresponding author for this work

Comprehensive Cancer Centre

Research output: Contribution to journal › Article › peer-review

68 Citations (Scopus)

Abstract

Purpose: To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and in different mouse tumor models. Experimental Design: We conducted a phase I trial in 36 patients with HCC (NCT02716012) who received sorafenib as part of their standard care, and were given therapeutic C/EBPα small activating RNA (saRNA; MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the preclinical setting, the effects of MTL-CEBPA were assessed in several mouse models, including BNL-1ME liver cancer, Lewis lung carcinoma (LLC), and colon adenocarcinoma (MC38). Results: MTL-CEBPA treatment caused radiologic regression of tumors in 26.7% of HCC patients with an underlying viral etiology with 3 complete responders. MTL-CEBPA treatment in those patients caused a marked decrease in peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers and an overall reduction in the numbers of protumoral M2 tumor-associated macrophages (TAM). Gene and protein analysis of patient leukocytes following treatment showed CEBPA activation affected regulation of factors involved in immune-suppressive activity. To corroborate this observation, treatment of all the mouse tumor models with MTL-CEBPA led to a reversal in the suppressive activity of M-MDSCs and TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor effects of MTL-CEBPA in these tumor models showed dependency on T cells. This was accentuated when MTL-CEBPA was combined with checkpoint inhibitors or with PMN-MDSC-targeted immunotherapy. Conclusions: This report demonstrates that therapeutic upregulation of the transcription factor C/EBPa causes inactivation of immune-suppressive myeloid cells with potent antitumor responses across different tumor models and in cancer patients. MTL-CEBPA is currently being investigated in combination with pembrolizumab in a phase I/Ib multicenter clinical study (NCT04105335).

Original language	English
Pages (from-to)	5961-5978
Number of pages	18
Journal	Clinical Cancer Research
Volume	27
Issue number	21
DOIs	https://doi.org/10.1158/1078-0432.CCR-21-0986
Publication status	Published - 15 Nov 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1158/1078-0432.CCR-21-0986

Cite this

Hashimoto, A., Sarker, D., Reebye, V., Jarvis, S., Sodergren, M. H., Kossenkov, A., Sanseviero, E., Raulf, N., Vasara, J., Andrikakou, P., Meyer, T., Huang, K. W., Plummer, R., Chee, C. E., Spalding, D., Pai, M., Khan, S., Pinato, D. J., Sharma, R., ... Gabrilovich, D. I. (2021). Upregulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and patients with cancer. Clinical Cancer Research, 27(21), 5961-5978. https://doi.org/10.1158/1078-0432.CCR-21-0986

@article{bbef9bf6fe4249e98e5ebe4366b62cdc,

title = "Upregulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and patients with cancer",

abstract = "Purpose: To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and in different mouse tumor models. Experimental Design: We conducted a phase I trial in 36 patients with HCC (NCT02716012) who received sorafenib as part of their standard care, and were given therapeutic C/EBPα small activating RNA (saRNA; MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the preclinical setting, the effects of MTL-CEBPA were assessed in several mouse models, including BNL-1ME liver cancer, Lewis lung carcinoma (LLC), and colon adenocarcinoma (MC38). Results: MTL-CEBPA treatment caused radiologic regression of tumors in 26.7% of HCC patients with an underlying viral etiology with 3 complete responders. MTL-CEBPA treatment in those patients caused a marked decrease in peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers and an overall reduction in the numbers of protumoral M2 tumor-associated macrophages (TAM). Gene and protein analysis of patient leukocytes following treatment showed CEBPA activation affected regulation of factors involved in immune-suppressive activity. To corroborate this observation, treatment of all the mouse tumor models with MTL-CEBPA led to a reversal in the suppressive activity of M-MDSCs and TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor effects of MTL-CEBPA in these tumor models showed dependency on T cells. This was accentuated when MTL-CEBPA was combined with checkpoint inhibitors or with PMN-MDSC-targeted immunotherapy. Conclusions: This report demonstrates that therapeutic upregulation of the transcription factor C/EBPa causes inactivation of immune-suppressive myeloid cells with potent antitumor responses across different tumor models and in cancer patients. MTL-CEBPA is currently being investigated in combination with pembrolizumab in a phase I/Ib multicenter clinical study (NCT04105335).",

author = "Ayumi Hashimoto and Debashis Sarker and Vikash Reebye and Sheba Jarvis and Sodergren, {Mikael H.} and Andrew Kossenkov and Emilio Sanseviero and Nina Raulf and Jenni Vasara and Pinelopi Andrikakou and Tim Meyer and Huang, {Kai Wen} and Ruth Plummer and Chee, {Cheng E.} and Duncan Spalding and Madhava Pai and Shahid Khan and Pinato, {David J.} and Rohini Sharma and Bristi Basu and Daniel Palmer and Ma, {Yuk Ting} and Jeff Evans and Robert Habib and Anna Martirosyan and Naouel Elasri and Adeline Reynaud and Rossi, {John J.} and Mark Cobbold and Habib, {Nagy A.} and Gabrilovich, {Dmitry I.}",

note = "Funding Information: D. Sarker reports non-financial support from MiNA Therapeutics during the conduct of the study. D. Sarker also reports personal fees and non-financial support from Ipsen and Eisai; personal fees from Bayer, AstraZeneca, Surface Oncology, MSD, Sirtex, and AAA; grants from UCB; and non-financial support from Medivir outside the submitted work. V. Reebye reports grants from MiNA Therapeutics Ltd during the conduct of the study, as well as other support from MiNA Therapeutics Ltd outside the submitted work. M.H. Sodergren reports grants from MiNA Therapeutics during the conduct of the study, as well as personal fees from Verb Robotics and EMMAC Life Sciences outside the submitted work. E. Sanseviero is currently a full-time employee of AstraZeneca. N. Raulf reports other support from MiNA Therapeutics Ltd during the conduct of the study, as well as other support from MiNA Therapeutics Ltd outside the submitted work. T. Meyer reports personal fees from Eisai, Ipsen, Roche, AstraZeneca, and Bayer outside the submitted work. R. Plummer reports other support from MiNA Therapeutics during the conduct of the study; R. Plummer also reports personal fees from Pierre Faber, Bayer, Novartis, Biosceptre, BMS, Cybrexa, Ellipses, CV6 Therapeutics, Astex Pharmaceuticals, Medivir, GammaDelta Therapeutics, Sanofi Aventis, and AstraZeneca, as well as other support from MSD outside the submitted work. D.J. Pinato reports personal fees from MiNA Therapeutics during the conduct of the study, as well as grants and personal fees from BMS, MSD, Eisai, Roche, Ipsen, AstraZeneca, DaVolterra, and Bayer outside the submitted work. R. Sharma reports grants from AAA Pharmaceuticals, Bayer, Astex Pharmaceuticals, Incyte Pharmaceuticals, and Boston Scientific, as well as other support from Esai, Sirtex, and Shingoi outside the submitted work. D. Palmer reports grants and personal fees from BMS, Sirtex, and Bayer, as well as personal fees from Eisai outside the submitted work. Y.-T. Ma reports personal fees from Ipsen, Roche, AstraZeneca, Eisai, Bayer, and Faron outside the submitted work. J. Evans reports other support from MiNA Therapeutics during the conduct of the study. J. Evans also reports other support from AstraZeneca, Bayer, Adaptimmune, Basilea, Starpharma, CytomX, Bicycle Therapeutics, Codiak, Boehringer, Verastem, Sierra, and Medivir; personal fees and other support from Eisai, MSD, Bristol-Myers Squibb, and Roche/Genentech; and personal fees from Pierre Fabre outside the submitted work. R. Habib reports personal fees from MiNA (Holdings) Limited during the conduct of the study. A. Martirosyan is a HalioDx employee and HalioDx is a service provider for MiNA Therapeutics. N. Elasri is a HalioDx employee and HalioDx is a service provider for Funding Information: This work was supported by Experimental Cancer Medicine Centres, NIHR Biomedical Research Centres, and NHS Trust Tissue Banks at Imperial College London, Newcastle University, Kings College London, University of Cambridge, University of Liverpool, University of Birmingham, University of Glasgow, and University College London. We thank Drs. DiRusso and Black (University of Nebraska) for providing lipofermata for our research of MDSC. This work was partially supported by Wistar Cancer Center Support NIH grant P50 CA168536. Funding for preclinical work was provided by MiNA Therapeutics. Publisher Copyright: {\textcopyright} 2021 The Authors; Published by the American Association for Cancer Research",

year = "2021",

month = nov,

day = "15",

doi = "10.1158/1078-0432.CCR-21-0986",

language = "English",

volume = "27",

pages = "5961--5978",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "21",

}

Hashimoto, A, Sarker, D, Reebye, V, Jarvis, S, Sodergren, MH, Kossenkov, A, Sanseviero, E, Raulf, N, Vasara, J, Andrikakou, P, Meyer, T, Huang, KW, Plummer, R, Chee, CE, Spalding, D, Pai, M, Khan, S, Pinato, DJ, Sharma, R, Basu, B, Palmer, D, Ma, YT, Evans, J, Habib, R, Martirosyan, A, Elasri, N, Reynaud, A, Rossi, JJ, Cobbold, M, Habib, NA & Gabrilovich, DI 2021, 'Upregulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and patients with cancer', Clinical Cancer Research, vol. 27, no. 21, pp. 5961-5978. https://doi.org/10.1158/1078-0432.CCR-21-0986

TY - JOUR

T1 - Upregulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and patients with cancer

AU - Hashimoto, Ayumi

AU - Sarker, Debashis

AU - Reebye, Vikash

AU - Jarvis, Sheba

AU - Sodergren, Mikael H.

AU - Kossenkov, Andrew

AU - Sanseviero, Emilio

AU - Raulf, Nina

AU - Vasara, Jenni

AU - Andrikakou, Pinelopi

AU - Meyer, Tim

AU - Huang, Kai Wen

AU - Plummer, Ruth

AU - Chee, Cheng E.

AU - Spalding, Duncan

AU - Pai, Madhava

AU - Khan, Shahid

AU - Pinato, David J.

AU - Sharma, Rohini

AU - Basu, Bristi

AU - Palmer, Daniel

AU - Ma, Yuk Ting

AU - Evans, Jeff

AU - Habib, Robert

AU - Martirosyan, Anna

AU - Elasri, Naouel

AU - Reynaud, Adeline

AU - Rossi, John J.

AU - Cobbold, Mark

AU - Habib, Nagy A.

AU - Gabrilovich, Dmitry I.

N1 - Funding Information: D. Sarker reports non-financial support from MiNA Therapeutics during the conduct of the study. D. Sarker also reports personal fees and non-financial support from Ipsen and Eisai; personal fees from Bayer, AstraZeneca, Surface Oncology, MSD, Sirtex, and AAA; grants from UCB; and non-financial support from Medivir outside the submitted work. V. Reebye reports grants from MiNA Therapeutics Ltd during the conduct of the study, as well as other support from MiNA Therapeutics Ltd outside the submitted work. M.H. Sodergren reports grants from MiNA Therapeutics during the conduct of the study, as well as personal fees from Verb Robotics and EMMAC Life Sciences outside the submitted work. E. Sanseviero is currently a full-time employee of AstraZeneca. N. Raulf reports other support from MiNA Therapeutics Ltd during the conduct of the study, as well as other support from MiNA Therapeutics Ltd outside the submitted work. T. Meyer reports personal fees from Eisai, Ipsen, Roche, AstraZeneca, and Bayer outside the submitted work. R. Plummer reports other support from MiNA Therapeutics during the conduct of the study; R. Plummer also reports personal fees from Pierre Faber, Bayer, Novartis, Biosceptre, BMS, Cybrexa, Ellipses, CV6 Therapeutics, Astex Pharmaceuticals, Medivir, GammaDelta Therapeutics, Sanofi Aventis, and AstraZeneca, as well as other support from MSD outside the submitted work. D.J. Pinato reports personal fees from MiNA Therapeutics during the conduct of the study, as well as grants and personal fees from BMS, MSD, Eisai, Roche, Ipsen, AstraZeneca, DaVolterra, and Bayer outside the submitted work. R. Sharma reports grants from AAA Pharmaceuticals, Bayer, Astex Pharmaceuticals, Incyte Pharmaceuticals, and Boston Scientific, as well as other support from Esai, Sirtex, and Shingoi outside the submitted work. D. Palmer reports grants and personal fees from BMS, Sirtex, and Bayer, as well as personal fees from Eisai outside the submitted work. Y.-T. Ma reports personal fees from Ipsen, Roche, AstraZeneca, Eisai, Bayer, and Faron outside the submitted work. J. Evans reports other support from MiNA Therapeutics during the conduct of the study. J. Evans also reports other support from AstraZeneca, Bayer, Adaptimmune, Basilea, Starpharma, CytomX, Bicycle Therapeutics, Codiak, Boehringer, Verastem, Sierra, and Medivir; personal fees and other support from Eisai, MSD, Bristol-Myers Squibb, and Roche/Genentech; and personal fees from Pierre Fabre outside the submitted work. R. Habib reports personal fees from MiNA (Holdings) Limited during the conduct of the study. A. Martirosyan is a HalioDx employee and HalioDx is a service provider for MiNA Therapeutics. N. Elasri is a HalioDx employee and HalioDx is a service provider for Funding Information: This work was supported by Experimental Cancer Medicine Centres, NIHR Biomedical Research Centres, and NHS Trust Tissue Banks at Imperial College London, Newcastle University, Kings College London, University of Cambridge, University of Liverpool, University of Birmingham, University of Glasgow, and University College London. We thank Drs. DiRusso and Black (University of Nebraska) for providing lipofermata for our research of MDSC. This work was partially supported by Wistar Cancer Center Support NIH grant P50 CA168536. Funding for preclinical work was provided by MiNA Therapeutics. Publisher Copyright: © 2021 The Authors; Published by the American Association for Cancer Research

PY - 2021/11/15

Y1 - 2021/11/15

N2 - Purpose: To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and in different mouse tumor models. Experimental Design: We conducted a phase I trial in 36 patients with HCC (NCT02716012) who received sorafenib as part of their standard care, and were given therapeutic C/EBPα small activating RNA (saRNA; MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the preclinical setting, the effects of MTL-CEBPA were assessed in several mouse models, including BNL-1ME liver cancer, Lewis lung carcinoma (LLC), and colon adenocarcinoma (MC38). Results: MTL-CEBPA treatment caused radiologic regression of tumors in 26.7% of HCC patients with an underlying viral etiology with 3 complete responders. MTL-CEBPA treatment in those patients caused a marked decrease in peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers and an overall reduction in the numbers of protumoral M2 tumor-associated macrophages (TAM). Gene and protein analysis of patient leukocytes following treatment showed CEBPA activation affected regulation of factors involved in immune-suppressive activity. To corroborate this observation, treatment of all the mouse tumor models with MTL-CEBPA led to a reversal in the suppressive activity of M-MDSCs and TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor effects of MTL-CEBPA in these tumor models showed dependency on T cells. This was accentuated when MTL-CEBPA was combined with checkpoint inhibitors or with PMN-MDSC-targeted immunotherapy. Conclusions: This report demonstrates that therapeutic upregulation of the transcription factor C/EBPa causes inactivation of immune-suppressive myeloid cells with potent antitumor responses across different tumor models and in cancer patients. MTL-CEBPA is currently being investigated in combination with pembrolizumab in a phase I/Ib multicenter clinical study (NCT04105335).

AB - Purpose: To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and in different mouse tumor models. Experimental Design: We conducted a phase I trial in 36 patients with HCC (NCT02716012) who received sorafenib as part of their standard care, and were given therapeutic C/EBPα small activating RNA (saRNA; MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the preclinical setting, the effects of MTL-CEBPA were assessed in several mouse models, including BNL-1ME liver cancer, Lewis lung carcinoma (LLC), and colon adenocarcinoma (MC38). Results: MTL-CEBPA treatment caused radiologic regression of tumors in 26.7% of HCC patients with an underlying viral etiology with 3 complete responders. MTL-CEBPA treatment in those patients caused a marked decrease in peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers and an overall reduction in the numbers of protumoral M2 tumor-associated macrophages (TAM). Gene and protein analysis of patient leukocytes following treatment showed CEBPA activation affected regulation of factors involved in immune-suppressive activity. To corroborate this observation, treatment of all the mouse tumor models with MTL-CEBPA led to a reversal in the suppressive activity of M-MDSCs and TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor effects of MTL-CEBPA in these tumor models showed dependency on T cells. This was accentuated when MTL-CEBPA was combined with checkpoint inhibitors or with PMN-MDSC-targeted immunotherapy. Conclusions: This report demonstrates that therapeutic upregulation of the transcription factor C/EBPa causes inactivation of immune-suppressive myeloid cells with potent antitumor responses across different tumor models and in cancer patients. MTL-CEBPA is currently being investigated in combination with pembrolizumab in a phase I/Ib multicenter clinical study (NCT04105335).

UR - http://www.scopus.com/inward/record.url?scp=85118374093&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-21-0986

DO - 10.1158/1078-0432.CCR-21-0986

M3 - Article

C2 - 34407972

AN - SCOPUS:85118374093

SN - 1078-0432

VL - 27

SP - 5961

EP - 5978

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 21

ER -

Upregulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and patients with cancer

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this