Tumor resection boosts therapeutic efficacy of encapsulated stem cells expressing a highly secretable variant of interferon-{beta} in glioblastomas

Purpose: Despite tumor resection being the frontline clinical care for glioblastoma (GBM) patients, nearly all preclinical immune therapy models intends to treat established GBM tumor. Characterizing cytoreductive surgery-induced immune-response combined with the administration of immune cytokines has the potential of offering a new treatment paradigm of immune therapy for GBMs.  Experimental design: We developed syngeneic orthotopic mouse GBM models of tumor-resection and characterized the immune response of intact and resected tumors. We also created a highly secretable variant of immune cytokine IFNβ to enhance the its release from engineered mouse mesenchymal stem cells (MSC-IFNβ) and assessed whether surgical resection of intracranial GBM tumor significantly enhance the anti-tumor efficacy of targeted on-site delivery of encapsulated-MSC-IFNβ. Results: We show that tumor debulking results in substantial reduction of myeloid-derived suppressor cells (MDSCs) and simultaneous recruitment of CD4/CD8 T cells. This immune response significantly enhanced the anti-tumor efficacy of locally delivered encapsulated-MSC-IFNβ. IFNβ enhanced selective post-surgical infiltration of CD8 T cells and directly induced cell-cycle arrest in tumor cells resulting in increased survival of mice. Utilizing encapsulated-MSC-IFNβ in resected orthotopic tumor xenografts of patient-derived GBM, we further show that IFNβ induces cell-cycle arrest followed by apoptosis resulting in increased survival in immune-compromised mice despite their absence of an intact immune system. Conclusions: This study demonstrates the importance of syngeneic tumor resection models in developing cancer immunotherapies and emphasizes the translational potential of local delivery of immune-therapeutic agents in treating cancer.

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