Glioblastoma (GBM) patients, one of the most deadly forms of human cancer, have not been benefited from the recent progress in immune checkpoint inhibitor-based immunotherapy mainly due to immune edition from aberrant dysregulation of gene expressions in tumor cells and poor innate immune response from tumor-supportive tumor microenvironment (TME) that is educated by tumor cell-secreting immunosuppressive cytokines. In order to prime the "cold" tumor cells and the immunosuppressive TME including tumor-associated macrophages (TAMs) to become sensitive to such attractive immunotherapy, their aberrantly deregulated gene expressions across various signaling pathways need to be reprogrammed by gl...

Read More

Glioblastoma (GBM) patients, one of the most deadly forms of human cancer, have not been benefited from the recent progress in immune checkpoint inhibitor-based immunotherapy mainly due to immune edition from aberrant dysregulation of gene expressions in tumor cells and poor innate immune response from tumor-supportive tumor microenvironment (TME) that is educated by tumor cell-secreting immunosuppressive cytokines. In order to prime the "cold" tumor cells and the immunosuppressive TME including tumor-associated macrophages (TAMs) to become sensitive to such attractive immunotherapy, their aberrantly deregulated gene expressions across various signaling pathways need to be reprogrammed by global gene expression regulators, such as microRNAs, since single miRNA generally regulates the expression of multiple target genes. We found that ectopic restoration of tumor suppressive miR-138 can revert GBM tumor cells and TAMs into treatable, through which overall survival in orthotopic xenograft mouse model can be significantly increased. However, clinical application of miRNA-based therapy has been hampered mainly due to the lack of efficient and safe targeted delivery method across the blood brain tumor barrier (BBTB). In recent years, we have shown a successful brain tumor targeting by using our novel RNA-driven nanovector (RNV), inspired and nanotechnologically engineered from three-way junction (3WJ) motif of packaging RNA (pRNA) in bacteriophage phi29 DNA packaging motor. Here, we propose to evaluate a preclinical therapeutic efficacy of RNV-mediated targeted delivery of miR-138 to reprogram both GBM tumor cells and TAMs in TME for successful combination with conventional immunotherapy. The outcomes from simultaneous modulation of both tumor cells and TAMs by targeted delivery of tumor suppressive miRNA using the RNV delivery system will accelerate the successful translation of miRNA-based GBM therapy for GBM patients through combination with immunotherapy.

Read Less