Researchers Develop Oncolytic Virus Based on Human Cytomegalovirus

Researchers at the Mayo Clinic published a research paper titled "Oncolytic cytomegaloviruses expressing EGFR-retargeted fusogenic glycoprotein complex and drug-controllable interleukin 12" in Cell Reports Medicine. This study developed an oncolytic human cytomegalovirus expressing an EGFR retargeting fusion gene glycoprotein complex and drug-controllable IL-12, and its significant anti-tumor effect was verified in glioblastoma (GBM) models.

Human cytomegalovirus (HCMV) is a member of the β-herpesvirus family with a double-stranded DNA genome of approximately 235 kb, encoding more than 200 open reading frames (ORFs). Its broad cellular tropism is regulated by the glycoprotein complex on the virus particle, among which the gH/gL/gO trimer complex (TC) helps the virus enter all susceptible cell types, while the gH/gL/pUL128-131 pentamer complex (PC) plays a key role in infecting non-fibroblasts.

HCMV has the potential to be developed as an oncolytic virus platform, showing promise in the treatment of gliomas and myeloid malignancies by effectively targeting cancer cells and cancer-associated myeloid cells. However, natural infection with wild-type HCMV usually results in a latent state that is insufficient to destroy tumor cells or stimulate a strong immune response. In order to transform HCMV into an effective oncolytic virus platform, the following modifications are required:

1. Delete the latent-related genes of HCMV, especially the genes in the UL/b' region;

2. Combine tumor targeting mechanisms to improve its ability to kill tumor cells;

3. Introduce pro-inflammatory transgenes.

In this latest study, the research team focused on recombining human cytomegalovirus (HCMV) into an oncolytic virus and evaluating its effectiveness in a glioblastoma (GBM) model.

In order to reduce virulence, the research team deleted the UL1-UL20 region (about 15kb) and the UL/b' sequence (about 13kb) from the HCMV genome. In order to enhance the targeting of HCMV to tumors, the research team equipped HCMV with an EGFR-retargeting fusion protein complex, which was modified from the detargeted paramyxovirus glycoprotein H/F. EGFR is expressed or amplified in a variety of tumors, including GBM. The EGFR-retargeted HEGFR/F glycoprotein complex significantly improves the oncolytic effect of HCMV-mediated GBM cells. In addition, the research team also added a Tet-off controlled IL-12 gene expression cassette to the HCMV genome to promote anti-tumor immune responses. Oncolytic HCMV carrying HEGFR/F and Tet-off controlled IL-12 showed significant anti-tumor efficacy in human glioblastoma xenograft models.

Figure 1. The AD169r-derived oncolytic viruses as CMV-based cancer viroimmunotherapy. (Jiang H, et al., 2024)

The research team also constructed oncolytic murine cytomegalovirus (mCMV) and evaluated its ability to induce anti-tumor immune responses in an immunocompetent glioblastoma mouse model, significantly increasing the abundance and cytotoxicity of CD4+ T cells, CD8+ T cells and CD4- CD8- T cells. These results highlight the potential of human cytomegalovirus as an oncolytic virus for viral immunotherapy of cancer.

Reference

Jiang H, et al. Oncolytic cytomegaloviruses expressing EGFR-retargeted fusogenic glycoprotein complex and drug-controllable interleukin 12. Cell Reports Medicine, 2024.