Immunological Effects and Viral Gene Expression Determine the Efficacy of Oncolytic Measles Vaccines Encoding IL-12 or IL-15 Agonists.

Backhaus Backhaus,Jeworowski Jeworowski,Poth Poth,Veinalde Veinalde,Albert Albert,Hartmann Hartmann,Engeland Engeland,Ungerechts Ungerechts,Jäger Jäger,Dunder Dunder,Hoyler Hoyler

doi:10.3390/v11100914

Abstract

Tumor-targeted immunomodulation using oncolytic viral vectors is currently being investigated as a promising strategy in cancer therapy. In a previous study, we showed that a measles virus Schwarz vaccine strain (MeVac) vector encoding an interleukin-12 fusion protein (FmIL-12) is an effective immunotherapy in the MC38cea murine colon adenocarcinoma model. We hypothesized that MeVac encoding interleukin-15 may mediate enhanced T and NK cell responses and thus increase the therapeutic efficacy, especially in NK cell-controlled tumors. Therefore, we generated MeVac vectors encoding an interleukin-15 superagonist, FmIL-15. Replication and oncolytic capacity, transgene expression, and functionality of MeVac FmIL-15 vectors were validated in vitro. Effects on the tumor immune landscape and therapeutic efficacy of both FmIL-12 and FmIL-15 vectors were studied in the MC38cea and B16hCD46 tumor models. Treatment with MeVac FmIL-15 increased T and NK cell infiltration in both models. However, MeVac FmIL-12 showed more robust viral gene expression and immune activation, resulting in superior anti-tumor efficacy. Based on these results, MeVac encoding a human IL-12 fusion protein was developed for future clinical translation.

Highlights

Oncolytic viruses (OVs) selectively replicate in malignant cells, leading to tumor cell lysis.Since viral replication and viral gene expression are confined to the malignant tissue, oncolytic viruses can be used as vectors for the delivery of therapeutic genes to the tumor site
While we found an increase in tumor-infiltrating activated T and NK cells after treatment with measles virus Schwarz vaccine strain (MeVac) FmIL-15, MeVac FmIL-12 proved to be superior in terms of tumor control and survival
This fusion protein consists of the murine IL-12 p40 and p35 subunits separated by a glycine-serine linker, as described by Lieschke et al [39]

Summary

Introduction

Since viral replication and viral gene expression are confined to the malignant tissue, oncolytic viruses can be used as vectors for the delivery of therapeutic genes to the tumor site Such therapeutic genes can include prodrug convertases, radiosensitizers, proapoptotic, or immunomodulatory molecules [1]. The latter concept is based on the fact that tumor cell death, in the context of viral infection, is highly immunogenic, due to the release of tumor antigens in concert with danger-associated and pathogen-associated molecular patterns (DAMPs and PAMPs). This can serve as an in situ tumor vaccine that elicits an anti-tumor immune response. Tumor-restricted expression, by means of an oncolytic vector, enables tumor immunomodulation with agents that can be highly toxic when administered systemically

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