Effect of a novel long-acting interleukin-7 agonist, NT-I7, on survival in mouse models of glioma.

e13516 Background: Glioblastoma is one of the most devastating cancers, with a 5-year overall survival < 10%. Patients are routinely treated with radiation therapy (RT) and temozolomide (TMZ). These treatments can cause prolonged severe lymphopenia which is associated with shorter survival. Interleukin-7 (IL-7) is a cytokine that preferentially supports growth and survival of CD4+ and CD8+ lymphocytes. IL-7 levels were inappropriately low in glioblastoma patients treated with chemoradiation who developed severe treatment-related lymphopenia (TRL). NT-I7 (rhIL-7-hyFc, from NeoImmuneTech, Inc.) is a long-acting cytokine consisting of recombinant human IL-7 fused to a hybrid Fc (hyFc) region of IgD and IgG4. Similarly to murine IL-7, human IL-7 also induces proliferation of murine cell lines. Consequently, NT-I7 can be studied using comparable dosing in both mice and humans. We hypothesized that administration of NT-I7 could mitigate TRL and improve survival. Methods: We developed a murine glioma model with chemoradiation induced lymphopenia. The C57BL/6 mice were injected intracranially with mouse glioma cells (GL261) expressing luciferase. Tumor-bearing mice were treated with clinically-relevant RT (2 Gy for 5 consecutive days) and concomitant TMZ (33mg/kg daily during RT) to induce lymphopenia. NT-I7 was given subcutaneously at 10 mg/kg one day after completion of RT/TMZ. Peripheral blood samples were collected on days 1, 3, 7, 14- and 28-days post-RT/TMZ. Lymphocyte counts including CD3, CD4, CD8, and CD19 were analyzed by flow cytometry. Tumor growth was monitored by bioluminescence imaging and mouse survival was monitored daily. Results: We found that 1) NT-I7 significantly improved lymphocyte count recovery post RT/TMZ; 2) mice receiving NT-I7 lived significantly longer than controls. Presently, we are elucidating the mechanisms of survival benefit found by NT-I7 administration. Conclusions: Overall, our data suggest that NT-I7 may be a feasible solution for immune reconstitution and may synergize anti-tumor effect with standard chemoradiation in glioma. Further studies are ongoing to confirm these findings in a different glioma model and to evaluate whether NT-I7 can alter tumor micro-environment.