Enhanced IL-12 transgene expression improves oncolytic viroimmunotherapy.

Area of Science:

• Oncology
• Virology
• Immunotherapy

Background:

• Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive and have poor prognoses, especially in neurofibromatosis 1 patients.
• Oncolytic viruses, specifically oncolytic Herpes Simplex Virus (oHSV), are being investigated as a potential immunotherapeutic strategy for MPNSTs.

Purpose of the Study:

• To compare the efficacy of unarmed and interleukin 12 (IL-12)-armed oHSVs in permissive and resistant MPNST models.
• To evaluate viral replication, functional activity, and host immune response to oHSV therapy in vivo and in vitro.

Main Methods:

• Two attenuated IL-12-armed oHSVs with γ134.5 gene deletions were compared: M002 and C002 (which expresses an HCMV IRS1 gene to evade translational arrest).
• Viral replication, transgene expression, and immune cell infiltration were assessed in virus-permissive (B109) and -resistant (67C-4) murine MPNST models.

Main Results:

• In vitro viral replication did not predict in vivo oncolytic activity; tumors resistant to viral replication in vivo also limited transgene expression.
• Despite similar transcriptional activity, oHSVs exhibited differential IL-12 protein production in vivo, impacting therapeutic outcomes.
• C002 treatment led to sustained IL-12 production, enhanced immune cell activity (dendritic cells, macrophages), and a polyfunctional Th1-cell response, resulting in greater tumor growth suppression.

Conclusions:

• Transgene protein production, not just viral replication, is critical for oHSV therapeutic efficacy in MPNSTs.
• IL-12 protein levels directly influence the anti-tumor immune response and therapeutic outcomes in oHSV-treated MPNSTs.