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.

Gene-edited and -engineered stem cell platform drives immunotherapy for brain metastatic melanomas

“…Allogeneic mesenchymal SCs can be easily obtained and banked and, following the good manufacturing practice (GMP) standards ( 62 ), offer “off-the-shelf” cellular therapy options for tumors. Our previous study with allogeneic human GMP grade SCs was performed to support an Investigational New Drug application, presented to the FDA to start a first-in-human (FIH) study ( 63 ). This FIH study of engineered SCs will assess safety and tolerability in patients with primary and recurrent glioblastoma after surgical resection.…”

Systems Medicine for Precise Targeting of Glioblastoma

“…In addition, in Pavon et al, it is suggested that the release of exosomes by MSCs can lead to tumor growth [ 103 ]. In Bhere et al, allogeneic MSCs which expressed cell-surface death receptor-targeted ligand were used to target GBM as kill switches [ 104 ]. In Menon et al, human bone marrow-derived MES stromal cells were engineered to produce tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) human as a therapeutic method in a mouse xenograft model which effectively inhibited GBM growth and prolonged survival [ 105 ].…”

Emerging extracellular vesicle-based carriers for glioblastoma diagnosis and therapy

“…Upon treatment with US at a power intensity of 1.5 W cm −2 in U87-tumor-bearing nude mice, the mice treated with CSI@Ex-A and US radiation exhibited significant tumor growth inhibition and tumor metastasis. Recently, an engineered macrophage exosome nanoplatform for GBM treatment was reported by Bhere et al 160 They used encapsulated and engineered allogeneic stem cells to identify target receptors for GBM therapy. The mesenchymal stem cells (MSC Bif ) was encapsulated inside HyStem-C hydrogel, termed EnMSC Bif .…”

“…This approach opens up new horizons for researchers using EVs for the treatment of GBMs. 160 Ferroptosis is a recently identified method of programmed cell death that is induced by excessive lipid peroxidation, and sheds light on GBM treatment strategies. It is known that glutathione peroxidase 4 (GPX4) is a crucial regulator of ferroptosis.…”