Targeting GD2-positive glioblastoma by chimeric antigen receptor empowered mesenchymal progenitors

Giulia Golinelli,Marco Bestagno,Filippo Rossignoli,Monica Cellini,Massimo Dominici,Giulia Grisendi,Edwin M Horwitz,Giacomo Pavesi,Carlotta Spano,Malvina Prapa,Franco Bambi,Alberto Feletti,Iacopo Sardi

doi:10.1038/s41417-018-0062-x

Abstract

Tumor targeting by genetically modified mesenchymal stromal/stem cells (MSCs) carrying anti-cancer molecules represents a promising cell-based strategy. We previously showed that the pro-apoptotic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can be successfully delivered by MSCs to cancer sites. While the interaction between TRAIL and its receptors is clear, more obscure is the way in which MSCs can selectively target tumors and their antigens. Several neuroectoderm-derived neoplasms, including glioblastoma (GBM), sarcomas, and neuroblastoma, express high levels of the tumor-associated antigen GD2. We have already challenged this cell surface disialoganglioside by a chimeric antigen receptor (CAR)-T cell approach against neuroblastoma. With the intent to maximize the therapeutic profile of MSCs delivering TRAIL, we here originally developed a bi-functional strategy where TRAIL is delivered by MSCs that are also gene modified with the truncated form of the anti-GD2 CAR (GD2 tCAR) to mediate an immunoselective recognition of GD2-positive tumors. These bi-functional MSCs expressed high levels of TRAIL and GD2 tCAR associated with a robust anti-tumor activity against GD2-positive GBM cells. Most importantly, the anti-cancer action was reinforced by the enhanced targeting potential of such bi-functional cells. Collectively, our results suggest that a truncated anti-GD2 CAR might be a powerful new tool to redirect MSCs carrying TRAIL against GD2-expressing tumors. This affinity-based dual targeting holds the promise to combine site-specific and prolonged retention of MSCs in GD2-expressing tumors, thereby providing a more effective delivery of TRAIL for still incurable cancers.

Highlights

Human mesenchymal stromal/stem cells (MSCs) are considered pivotal players in cellular therapy
The presence of membrane-bound TRAIL (mTRAIL) and GD2 tCAR molecules was verified by fluorescence-activated cell sorter (FACS) on transduced MSCs (Fig. 1b)
tumor necrosis factor-related apoptosisinducing ligand (TRAIL) and GD2 tCAR were undetectable on EV MSCs (Fig. 1b, row 1), while GD2 tCAR was exclusively revealed in 79 ± 7% of GD2 tCAR MSCs (Fig. 1b, row 2)

Summary

Introduction

Human mesenchymal stromal/stem cells (MSCs) are considered pivotal players in cellular therapy. Their isolation easiness from different sources and their capacity to be engineered by viral vectors make them cellular vehicles to deliver anti-tumor agents [1]. As putative tumor stroma cell precursors, MSCs can localize within tumors by promising. Once to the tumor site, they can offer a prolonged and concentrated local delivery of therapeutic molecules, reducing a nonselective targeting to possibly improve efficacy of standard treatments [3]. Glioblastoma (GBM) is the most common primary malignant brain tumor in human. Despite considerable advances in therapies, GBM remains one of the most challenging diseases [4]. Novel strategies based on oncolytic viral vectors have difficulties in reaching metastatic niches from the main tumor burden [6, 7]

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Results

Conclusion