(P 125) MYELOMODULATORY TREATMENTS AUGMENT THE THERAPEUTIC BENEFIT OF ONCOLYTIC VIRUS IN MALIGNANT PERIPHERAL NERVE SHEATH TUMORS BY MODULATING THE TUMOR MICROENVIRONMENT

Objective: The immunosuppressive microenvironment remains a key challenge for advancing immune-based strategies in targeting solid tumors. This study aimed to investigate whether rational targeting of the myeloid cells in Malignant Peripheral Nerve Sheath Tumors (MPNST) could potentiate the effectiveness of oncolytic herpes simplex viroimmunotherapy.

Methods: We employed whole genome RNA sequencing to characterize murine MPNST models at baseline. In two preclinical mouse models of MPNST, we combined the oncolytic virus T-VEC with myeloid-cell targeting therapeutics, Pexidartinib or Trabectedin, to assess the combination therapy's antitumor efficacy and survival benefits. Antibody-induced cell depletion was utilized to evaluate if the observed survival benefits were immune-mediated. Additionally, Flow cytometry was employed to investigate treatment-induced changes in the tumor microenvironment, including immune cell infiltration and immune cell phenotypes.

Results: Monotherapy with oncolytic herpes simplex viruses demonstrated modest efficacy. However, combining T-VEC with myelomodulatory therapies, namely pexidartinib or trabectedin, significantly increased survival in immunocompetent C57BL/6 or Balb/c tumor models, respectively, albeit complete tumor regressions were not achieved. Notably, the survival benefit diminished upon combining T-VEC and Trabectedin with antibodies targeting CD4 and CD8 T cells, underscoring the dependence on CD4 and CD8 T cells for the enhanced therapeutic effect. Subsequent flow cytometry analysis of mice treated with the T-VEC and trabectedin combination revealed a notable increase in the proportion of tumor-associated retrovirus antigen-specific CD8 T cells, targeting the envelope glycoprotein gp70, compared to monotherapy groups receiving T-VEC or trabectedin alone. Furthermore, there was a decrease in the proportions of M2 macrophages and myeloid-derived suppressor cells while increasing the M1/M2 ratio within the virus-treated and combination therapy cohorts.

Conclusion: Our findings provide compelling evidence that myelomodulatory therapies can augment the antitumor T-cell response and improve the therapeutic benefits of oncolytic virotherapy in murine models of MPNST. These results provide valuable insights for designing and implementing future immunotherapeutic strategies in the management of MPNST.