Exth-52. long-acting recombinant interleukin-7, nt-i7, improves survival following oncolytic zika virus treatment in the sb28 immunosuppressive and treatment-resistant murine glioma model

Abstract Glioblastoma (GBM) does not respond to immunotherapy for several reasons, including limited cancer-specific neoantigens and poor T-cell infiltration. The SB28 murine glioma model recapitulates these aspects of human GBM. Zika virus (ZIKV) treatment of GL261 and CT2A-bearing mice resulted in significant survival improvement through multiple mechanisms, including direct tumor killing and induction of a local CD8+ T-cell anti-tumor response, but ZIKV is less effective against SB28 tumors. Previously, we published that a long-acting human IL-7, rhIL-7-hyFc (NT-I7, efineptakin alfa; NeoImmuneTech Inc.), increases T-cell abundance and improves tumor infiltration. Therefore, we hypothesize that combining NT-I7 with oncolytic ZIKV therapy will enhance the anti-tumor response and improve survival in mice bearing SB28 syngeneic tumors. 1×103 SB28 tumor cells were intracranially implanted in C57BL/6J mice. Mice were treated with NT-I7 on post tumor implantation day 7 and 10, followed by intratumoral ZIKV on day 14. Tumor burden was assessed using bioluminescence imaging; mice were monitored for survival and bled weekly to assess the systemic T-cell response to NT-I7. Subcutaneous injection of NT-I7 significantly boosted systemic T-cell abundance compared to control (5,623 cells/uL vs. 136 cells/uL, p < 0.05), particularly cytotoxic CD8+ T-cells (4,776 cells/uL vs. 47 cells/uL, p < 0.05). This increased abundance of CD8+ T-cells peaked at 7 days after initial treatment and persisted for 21 days. NT-I7 monotherapy did not confer any survival benefit. However, the combination of NT-I7 and ZIKV treatment resulted in significant improvement in survival compared to NT-I7 or ZIKV treatment alone (p < 0.05). Treatment with NT-I7 primes the immune system by expanding the circulating CD8+ T-cell population by 100-fold. Timing the oncolytic ZIKV injection with the peak in peripheral CD8+ T-cells greatly improved survival in the immunotherapy resistant SB28 glioma model. These data suggest a role for NT-I7 as an adjunct to various T-cell mediated treatment strategies for GBM.