Abstract
Mesenchymal stem cells (MSCs) show an inherent brain tumor cell 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. Apceth-301 is a cell-based immunotherapy consisting of MSCs which are genetically modified to co-express high levels of IL-12 and IL-7. In vitro characterization demonstrated increased T-cell activation, as measured by increased secretion of IFNg and TNFa, and promoted NK cell mediated killing of GBM cell lines in co-culture assays. Therapeutic efficacy was assessed in two immunocompetent orthotopic C57BL/6 glioma models using GL261 and CT2A. Intratumoral administration of MSCIL7/12 induced a significant tumor growth inhibition and displayed tumor necrosis MR imaging. Notably, up to 50% of treated mice survived long-term. Re-challenging of survivors confirmed long-lasting tumor immunity. Immunomodulatory effects were assessed by immunehistology and multicolor flow-cytometry to comprehensively profile immune activation of tumor-infiltrating lymphocytes (TIL). Local treatment with MSC-IL12/7 was well tolerated and led to a significant inversion of CD4+/CD8+ T-cell ratio with an intricate predominantly CD8+ T-cell mediated anti-tumor response. T-cell receptor sequencing demonstrated 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. 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.