Interleukin 12 Secretion Enhances Antitumor Efficacy of Oncolytic Herpes Simplex Viral Therapy for Colorectal Cancer

Abstract

ObjectiveTo assess the strategy of combining oncolytic herpes simplex virus (HSV) therapy with immunomodulatory therapy as treatment for experimental colon cancer. The oncolytic HSV recombinant NV1023 and the interleukin 12 (IL-12)-secreting oncolytic NV1042 virus were evaluated in vitro and in vivo with respect to antitumor efficacy. Summary Background DataGenetically engineered, replication-conditional, attenuated HSVs have shown oncolytic activity against a wide variety of solid malignancies. Other strategies for treating cancer have involved immunomodulation and cytokine gene transfer using viral vectors. This study has combined both of these strategies by inserting the murine IL-12 gene into a replication-competent HSV. This approach allows oncolytic therapy to replicate selectively within and lyse tumor cells while providing the host immune system with the cytokine stimulus necessary to recruit and activate inflammatory cells needed to enhance the antitumor effect. MethodsNV1023 is a multimutant HSV based on the wild-type HSV-1 F strain. NV1042 was created by insertion of the mIL-12 gene into NV1023. Cytotoxicity and viral proliferation of both NV1023 and NV1042 within murine CT26 colorectal cancer cells were first shown. Cells infected with NV1042 were then shown to produce significant levels of IL-12. Using an experimental flank model of colon cancer, mice were treated with both high and low doses of NV1023 or NV1042 and were followed up for both cure and reduction in tumor burden.

ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties

“…While a number of cytokines have been considered for use in anti-tumour therapy (including the use of GM-CSF or IL12 in oncolytic HSV vectors [39][40][41][42][43] ), GM-CSF has generally, and most reliably, given the best results when tested in comparison to other cytokines in pre-clinical models. Clinically, for cancer treatment, indications of efficacy have also been seen when GM-CSF has been delivered by a number of means (eg using engineered, re-injected primary tumour cells -'GVAX'; eg reference 44).…”

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

“…A number of preclinical studies have shown that oncolytic herpes viruses induce cytotoxic T lymphocyte-mediated antitumor immunity, which can inhibit tumor regrowth upon rechallenge. [33][34][35][36] Consistent with this, efforts have been made to arm oncolytic herpes viruses with cytokines such as interleukin-12 37 and granulocyte-macrophage colony-stimulating factor 10,38 in order to intensify antitumor immunity. From this perspective, it might be said that the potency of a virus relies on its capacity to induce antitumor immunity.…”

Neoadjuvant treatment of hepatic malignancy: an oncolytic herpes simplex virus expressing IL-12 effectively treats the parent tumor and protects against recurrence-after resection

“…Preliminary work suggests that combined immunostimulatory and oncolytic therapy enhances tumor cell kill. 33 In the present experiments, NV1042, a replication competent, oncolytic HSV expressing IL-12, was used to treat established hepatic tumors prior to resection. IL-12 was chosen because of its broad and potent immunostimulatory activity.…”