Tumor resection recruits effector T cells and boosts therapeutic efficacy of encapsulated stem cells expressing IFNβ in glioblastomas

Purpose: Despite tumor resection being the first-line clinical care for glioblastoma (GBM) patients, nearly all preclinical immune therapy models intend to treat established GBM. 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 its release from engineered mouse mesenchymal stem cells (MSC-IFNβ) and assessed whether surgical resection of intracranial GBM tumor significantly enhanced the antitumor 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 (MDSC) and simultaneous recruitment of CD4/CD8 T cells. This immune response significantly enhanced the antitumor efficacy of locally delivered encapsulated MSC-IFNβ via enhanced selective postsurgical infiltration of CD8 T cells and directly induced cell-cycle arrest in tumor cells, resulting in increased survival of mice. Utilizing encapsulated human 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 immunocompromised 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 immunotherapeutic agents in treating cancer.