Target receptor identification and subsequent treatment of resected brain tumors with encapsulated and engineered allogeneic stem cells

Deepak Bhere; Sung Hugh Choi; Pim van de Donk; David Hope; Kiki Gortzak; Amina Kunnummal; Jasneet Khalsa; Esther Revai Lechtich; Clemens Reinshagen; Victoria Leon; Nabil Nissar; Wenya Linda Bi; Cheng Feng; Hongbin Li; Yu Shrike Zhang; Steven H. Liang; Neil Vasdev; Walid Ibn Essayed; Pablo Valdes Quevedo; Alexandra Golby; Naima Banouni; Anna Palagina; Reza Abdi; Brian Fury; Stelios Smirnakis; Alarice Lowe; Brock Reeve; Arthur Hiller; E. Antonio Chiocca; Glenn Prestwich; Hiroaki Wakimoto; Gerhard Bauer; Khalid Shah

doi:10.1038/s41467-022-30558-3

Target receptor identification and subsequent treatment of resected brain tumors with encapsulated and engineered allogeneic stem cells

Deepak Bhere, Sung Hugh Choi, Pim van de Donk, David Hope, Kiki Gortzak, Amina Kunnummal, Jasneet Khalsa, Esther Revai Lechtich, Clemens Reinshagen, Victoria Leon, Nabil Nissar, Wenya Linda Bi, Cheng Feng, Hongbin Li, Yu Shrike Zhang, Steven H. Liang, Neil Vasdev, Walid Ibn Essayed, Pablo Valdes Quevedo, Alexandra GolbyNaima Banouni, Anna Palagina, Reza Abdi, Brian Fury, Stelios Smirnakis, Alarice Lowe, Brock Reeve, Arthur Hiller, E. Antonio Chiocca, Glenn Prestwich, Hiroaki Wakimoto, Gerhard Bauer, Khalid Shah

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

7 Scopus citations

Abstract

Cellular therapies offer a promising therapeutic strategy for the highly malignant brain tumor, glioblastoma (GBM). However, their clinical translation is limited by the lack of effective target identification and stringent testing in pre-clinical models that replicate standard treatment in GBM patients. In this study, we show the detection of cell surface death receptor (DR) target on CD146-enriched circulating tumor cells (CTC) captured from the blood of mice bearing GBM and patients diagnosed with GBM. Next, we developed allogeneic “off-the-shelf” clinical-grade bifunctional mesenchymal stem cells (MSC^Bif) expressing DR-targeted ligand and a safety kill switch. We show that biodegradable hydrogel encapsulated MSC^Bif (EnMSC^Bif) has a profound therapeutic efficacy in mice bearing patient-derived invasive, primary and recurrent GBM tumors following surgical resection. Activation of the kill switch enhances the efficacy of MSC^Bif and results in their elimination post-tumor treatment which can be tracked by positron emission tomography (PET) imaging. This study establishes a foundation towards a clinical trial of EnMSC^Bif in primary and recurrent GBM patients.

Original language	English (US)
Article number	2810
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30558-3
State	Published - Dec 2022
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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Bhere, D., Choi, S. H., van de Donk, P., Hope, D., Gortzak, K., Kunnummal, A., Khalsa, J., Revai Lechtich, E., Reinshagen, C., Leon, V., Nissar, N., Bi, W. L., Feng, C., Li, H., Zhang, Y. S., Liang, S. H., Vasdev, N., Essayed, W. I., Quevedo, P. V., ... Shah, K. (2022). Target receptor identification and subsequent treatment of resected brain tumors with encapsulated and engineered allogeneic stem cells. Nature communications, 13(1), Article 2810. https://doi.org/10.1038/s41467-022-30558-3

Bhere, D, Choi, SH, van de Donk, P, Hope, D, Gortzak, K, Kunnummal, A, Khalsa, J, Revai Lechtich, E, Reinshagen, C, Leon, V, Nissar, N, Bi, WL, Feng, C, Li, H, Zhang, YS, Liang, SH, Vasdev, N, Essayed, WI, Quevedo, PV, Golby, A, Banouni, N, Palagina, A, Abdi, R, Fury, B, Smirnakis, S, Lowe, A, Reeve, B, Hiller, A, Chiocca, EA, Prestwich, G, Wakimoto, H, Bauer, G & Shah, K 2022, 'Target receptor identification and subsequent treatment of resected brain tumors with encapsulated and engineered allogeneic stem cells', Nature communications, vol. 13, no. 1, 2810. https://doi.org/10.1038/s41467-022-30558-3

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title = "Target receptor identification and subsequent treatment of resected brain tumors with encapsulated and engineered allogeneic stem cells",

abstract = "Cellular therapies offer a promising therapeutic strategy for the highly malignant brain tumor, glioblastoma (GBM). However, their clinical translation is limited by the lack of effective target identification and stringent testing in pre-clinical models that replicate standard treatment in GBM patients. In this study, we show the detection of cell surface death receptor (DR) target on CD146-enriched circulating tumor cells (CTC) captured from the blood of mice bearing GBM and patients diagnosed with GBM. Next, we developed allogeneic “off-the-shelf” clinical-grade bifunctional mesenchymal stem cells (MSCBif) expressing DR-targeted ligand and a safety kill switch. We show that biodegradable hydrogel encapsulated MSCBif (EnMSCBif) has a profound therapeutic efficacy in mice bearing patient-derived invasive, primary and recurrent GBM tumors following surgical resection. Activation of the kill switch enhances the efficacy of MSCBif and results in their elimination post-tumor treatment which can be tracked by positron emission tomography (PET) imaging. This study establishes a foundation towards a clinical trial of EnMSCBif in primary and recurrent GBM patients.",

author = "Deepak Bhere and Choi, {Sung Hugh} and {van de Donk}, Pim and David Hope and Kiki Gortzak and Amina Kunnummal and Jasneet Khalsa and {Revai Lechtich}, Esther and Clemens Reinshagen and Victoria Leon and Nabil Nissar and Bi, {Wenya Linda} and Cheng Feng and Hongbin Li and Zhang, {Yu Shrike} and Liang, {Steven H.} and Neil Vasdev and Essayed, {Walid Ibn} and Quevedo, {Pablo Valdes} and Alexandra Golby and Naima Banouni and Anna Palagina and Reza Abdi and Brian Fury and Stelios Smirnakis and Alarice Lowe and Brock Reeve and Arthur Hiller and Chiocca, {E. Antonio} and Glenn Prestwich and Hiroaki Wakimoto and Gerhard Bauer and Khalid Shah",

note = "Funding Information: We would like to thank Alex Schambach for kindly providing the pRRL.ppt.EFS.GFP vector and was obtained under a Material Transfer Agreement. We would like to thank Oskar Nowicki for assistance with the Time Lapse Imaging. All illustrations have been created for this manuscript using BioRender with a license to use the illustrations (D.B., K.S.). We thank the NeuroTechnology Studio at Brigham and Women{\textquoteright}s Hospital for providing the InCell analyzer and Mesoscope instrument access and consultation on data acquisition and data analysis. This study was supported by Research Fund (to K.S.) and AMASA Therapeutics. Funding Information: We would like to thank Alex Schambach for kindly providing the pRRL.ppt.EFS.GFP vector and was obtained under a Material Transfer Agreement. We would like to thank Oskar Nowicki for assistance with the Time Lapse Imaging. All illustrations have been created for this manuscript using BioRender with a license to use the illustrations (D.B., K.S.). We thank the NeuroTechnology Studio at Brigham and Women{\textquoteright}s Hospital for providing the InCell analyzer and Mesoscope instrument access and consultation on data acquisition and data analysis. This study was supported by Research Fund (to K.S.) and AMASA Therapeutics. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-30558-3",

language = "English (US)",

volume = "13",

journal = "Nature communications",

issn = "2041-1723",

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number = "1",

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T1 - Target receptor identification and subsequent treatment of resected brain tumors with encapsulated and engineered allogeneic stem cells

AU - Bhere, Deepak

AU - Choi, Sung Hugh

AU - van de Donk, Pim

AU - Hope, David

AU - Gortzak, Kiki

AU - Kunnummal, Amina

AU - Khalsa, Jasneet

AU - Revai Lechtich, Esther

AU - Reinshagen, Clemens

AU - Leon, Victoria

AU - Nissar, Nabil

AU - Bi, Wenya Linda

AU - Feng, Cheng

AU - Li, Hongbin

AU - Zhang, Yu Shrike

AU - Liang, Steven H.

AU - Vasdev, Neil

AU - Essayed, Walid Ibn

AU - Quevedo, Pablo Valdes

AU - Golby, Alexandra

AU - Banouni, Naima

AU - Palagina, Anna

AU - Abdi, Reza

AU - Fury, Brian

AU - Smirnakis, Stelios

AU - Lowe, Alarice

AU - Reeve, Brock

AU - Hiller, Arthur

AU - Chiocca, E. Antonio

AU - Prestwich, Glenn

AU - Wakimoto, Hiroaki

AU - Bauer, Gerhard

AU - Shah, Khalid

N1 - Funding Information: We would like to thank Alex Schambach for kindly providing the pRRL.ppt.EFS.GFP vector and was obtained under a Material Transfer Agreement. We would like to thank Oskar Nowicki for assistance with the Time Lapse Imaging. All illustrations have been created for this manuscript using BioRender with a license to use the illustrations (D.B., K.S.). We thank the NeuroTechnology Studio at Brigham and Women’s Hospital for providing the InCell analyzer and Mesoscope instrument access and consultation on data acquisition and data analysis. This study was supported by Research Fund (to K.S.) and AMASA Therapeutics. Funding Information: We would like to thank Alex Schambach for kindly providing the pRRL.ppt.EFS.GFP vector and was obtained under a Material Transfer Agreement. We would like to thank Oskar Nowicki for assistance with the Time Lapse Imaging. All illustrations have been created for this manuscript using BioRender with a license to use the illustrations (D.B., K.S.). We thank the NeuroTechnology Studio at Brigham and Women’s Hospital for providing the InCell analyzer and Mesoscope instrument access and consultation on data acquisition and data analysis. This study was supported by Research Fund (to K.S.) and AMASA Therapeutics. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Cellular therapies offer a promising therapeutic strategy for the highly malignant brain tumor, glioblastoma (GBM). However, their clinical translation is limited by the lack of effective target identification and stringent testing in pre-clinical models that replicate standard treatment in GBM patients. In this study, we show the detection of cell surface death receptor (DR) target on CD146-enriched circulating tumor cells (CTC) captured from the blood of mice bearing GBM and patients diagnosed with GBM. Next, we developed allogeneic “off-the-shelf” clinical-grade bifunctional mesenchymal stem cells (MSCBif) expressing DR-targeted ligand and a safety kill switch. We show that biodegradable hydrogel encapsulated MSCBif (EnMSCBif) has a profound therapeutic efficacy in mice bearing patient-derived invasive, primary and recurrent GBM tumors following surgical resection. Activation of the kill switch enhances the efficacy of MSCBif and results in their elimination post-tumor treatment which can be tracked by positron emission tomography (PET) imaging. This study establishes a foundation towards a clinical trial of EnMSCBif in primary and recurrent GBM patients.

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ER -

Target receptor identification and subsequent treatment of resected brain tumors with encapsulated and engineered allogeneic stem cells

Abstract

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