Nature Communications (May 2022)

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
https://doi.org/10.1038/s41467-022-30558-3
Journal volume & issue
Vol. 13, no. 1
pp. 1 – 16

Abstract

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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.