Mohme, Malte and Maire, Cecile L. and Geumann, Ulf and Schliffke, Simon and Duehrsen, Lasse and Fita, Krystian and Akyuez, Nuray and Binder, Mascha and Westphal, Manfred and Guenther, Christine and Lamszus, Katrin and Hermann, Felix G. and Schmidt, Nils Ole (2020) Local Intracerebral Immunomodulation Using Interleukin-Expressing Mesenchymal Stem Cells in Glioblastoma. CLINICAL CANCER RESEARCH, 26 (11). pp. 2626-2639. ISSN 1078-0432, 1557-3265
Full text not available from this repository. (Request a copy)Abstract
Purpose: Mesenchymal stem cells (MSCs) show an inherent brain tumor tropism that can be exploited for targeted delivery of therapeutic genes to invasive glioma. We assessed whether a motile MSC-based local immunomodulation is able to overcome the immunosuppressive glioblastoma microenvironment and to induce an antitumor immune response. Experimental Design: We genetically modified MSCs to coexpress high levels of IL12 and IL7 (MSCIL7/12, Apceth-301). Therapeutic efficacy was assessed in two immunocompetent orthotopic C57BL/6 glioma models using GL261 and CT2A. Immunomodulatory effects were assessed by multicolor flow cytometry to profile immune activation and exhaustion of tumor-infiltrating immune cells. Diversity of the tumor-specific immune response as analyzed using T-cell receptor sequencing. Results: Intratumoral administration of MSCIL7/12 induced significant tumor growth inhibition and remission of established intracranial tumors, as demonstrated by MR imaging. Notably, up to 50% of treated mice survived long-term. Rechallenging of survivors confirmed long-lasting tumor immunity. Local treatment with MSCIL7/12 was well tolerated and led to a significant inversion of the CD4(+)/CD8(+)n T-cell ratio with an intricate, predominantly CD8(+) effector T-cell-mediated antitumor response. T-cell receptor sequencing demonstrated an increased diversity of TILs in MSCIL7/12-treated mice, indicating a broader tumor-specific immune response with subsequent oligoclonal specification during generation of long-term immunity. Conclusions: Local MSC-based immunomodulation is able to efficiently alter the immunosuppressive microenvironment in glioblastoma. The long-lasting therapeutic effects warrant a rapid clinical translation of this concept and have led to planning of a phase I/II study of apceth-301 in recurrent glioblastoma.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BONE-MARROW; BETA-CHAINS; T-CELLS; LIGANDS; IL-7; PROLIFERATION; INHIBITION; CONTRIBUTE; DIVERSITY; MECHANISM; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Neurochirurgie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Mar 2021 12:04 |
| Last Modified: | 22 Mar 2021 12:04 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44486 |
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