Local Delivery of an IL-15 Superagonist Using a Replicating Retrovirus Improves Survival and Lymphocyte Infiltration in Poorly Immunogenic Mouse Models of Glioblastoma

ABSTRACT: Glioblastoma (GBM) leads to severe systemic and local immunosuppression, and immunotherapies have had limited success. One of the hallmarks of GBM immunosuppression is poor T cell infiltration and significant intratumoral T cell dysfunction. IL-15 is a promising immunocytokine with the ability to stimulate T cell activation and proliferation. In this study, we evaluate the treatment efficacy of RLI (an IL-15 superagonist) delivered to tumor cells using a tumor-selective retroviral replicating vector (RRV) in the poorly immunogenic syngeneic murine SB28 and Tu2449 models of GBM. RRV-RLI replicates and spreads effectively in cultured SB28 cells. Transduced SB28 cells express high levels of RLI (175 ng/mL), which sustained T cell growth in culture. Treatment with RRV-RLI by stereotactic injection into intracerebral murine SB28 and Tu2449 tumors significantly reduced tumor growth on bioluminescence imaging, and increased survival relative to control mice, leading to long-term survival in a subset of treated mice. RRV-RLI treated tumors showed significantly increased CD4 and CD8 T cell infiltration, without changes in immunosuppressive cell populations, including myeloid-derived suppressor cells or T regulatory cells. This study demonstrates that localized tumor-specific immunomodulatory gene therapy delivered in an RRV has the potential to safely reverse the T-cell depleted immunophenotype of GBM.

ORGANISM(S): Mus musculus

PROVIDER: GSE278988 | GEO | 2024/11/01

REPOSITORIES: GEO