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

Nat Commun. 2022 May 19;13(1):2810. doi: 10.1038/s41467-022-30558-3.

Authors

Deepak Bhere^{1

2

3}, Sung Hugh Choi^{1

2}, Pim van de Donk^{1

4}, David Hope^{1

2}, Kiki Gortzak^{1

4}, Amina Kunnummal^{1

4}, Jasneet Khalsa^{1

2}, Esther Revai Lechtich^{1

2}, Clemens Reinshagen^{1

2}, Victoria Leon^{1

2}, Nabil Nissar^{1

4}, Wenya Linda Bi², Cheng Feng⁵, Hongbin Li⁵, Yu Shrike Zhang⁵, Steven H Liang⁴, Neil Vasdev⁴, Walid Ibn Essayed², Pablo Valdes Quevedo², Alexandra Golby², Naima Banouni⁶, Anna Palagina⁷, Reza Abdi⁶, Brian Fury⁸, Stelios Smirnakis⁷, Alarice Lowe^{9

10}, Brock Reeve¹¹, Arthur Hiller¹², E Antonio Chiocca², Glenn Prestwich^{13

14}, Hiroaki Wakimoto^{1

2

15}, Gerhard Bauer⁸, Khalid Shah^{16

17

18}

Affiliations

¹ Center for Stem Cell and Translational Immunotherapy (CSTI), Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
² Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
³ Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29201, USA.
⁴ Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02115, USA.
⁵ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
⁶ Department of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
⁷ Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
⁸ UC Davis Institute for Regenerative Cures, Davis, CA, 95817, USA.
⁹ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
¹⁰ Department of Pathology, Stanford University, Stanford, CA, 94305, USA.
¹¹ Harvard Stem Cell Institute, Harvard University, Cambridge, MA, 02138, USA.
¹² Amasa Therapeutics Inc., 1 Harmony Lane, Andover, MA, 01810, USA.
¹³ Department of Medicinal Chemistry, College of Pharmacy University of Utah, Salt Lake City, UT, 84112, USA.
¹⁴ Washington State University Health Sciences, Spokane, WA, 99202, USA.
¹⁵ Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
¹⁶ Center for Stem Cell and Translational Immunotherapy (CSTI), Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. kshah@bwh.harvard.edu.
¹⁷ Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. kshah@bwh.harvard.edu.
¹⁸ Harvard Stem Cell Institute, Harvard University, Cambridge, MA, 02138, USA. kshah@bwh.harvard.edu.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Neoplasms* / drug therapy
Brain Neoplasms* / therapy
Cell Line, Tumor
Glioblastoma* / drug therapy
Glioblastoma* / therapy
Hematopoietic Stem Cell Transplantation*
Humans
Mice
Neoplasm Recurrence, Local / therapy