Local intracerebral immunomodulation using interleukin-expressing mesenchymal stem cells in glioblastoma
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Local intracerebral immunomodulation using interleukin-expressing mesenchymal stem cells in glioblastoma. / Mohme, Malte; Maire, Cecile L; Geumann, Ulf; Schliffke, Simon; Dührsen, Lasse; Fita, Krystian D; Akyüz, Nuray; Binder, Mascha; Westphal, Manfred; Guenther, Christine; Lamszus, Katrin; Hermann, Felix G; Schmidt, Nils Ole.
In: CLIN CANCER RES, Vol. 26, No. 11, 01.06.2020, p. 2626-2639.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Local intracerebral immunomodulation using interleukin-expressing mesenchymal stem cells in glioblastoma
AU - Mohme, Malte
AU - Maire, Cecile L
AU - Geumann, Ulf
AU - Schliffke, Simon
AU - Dührsen, Lasse
AU - Fita, Krystian D
AU - Akyüz, Nuray
AU - Binder, Mascha
AU - Westphal, Manfred
AU - Guenther, Christine
AU - Lamszus, Katrin
AU - Hermann, Felix G
AU - Schmidt, Nils Ole
N1 - ©2020 American Association for Cancer Research.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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+ 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.
AB - 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+ 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.
U2 - 10.1158/1078-0432.CCR-19-0803
DO - 10.1158/1078-0432.CCR-19-0803
M3 - SCORING: Journal article
C2 - 31988196
VL - 26
SP - 2626
EP - 2639
JO - CLIN CANCER RES
JF - CLIN CANCER RES
SN - 1078-0432
IS - 11
ER -