Herpes Virus Targets Metastatic Melanomas in the Brain

Stem cells loaded with oncolytic herpes simplex virus significantly slowed tumor growth in mice.

A novel method that harnesses the power of viruses shows promise targeting skin cancer metastases in the brain.

In a study published in PNAS, the investigators developed cancer-killing viruses that can deliver stem cells via the carotid artery.

A population of bone marrow derived from mesenchymal stem cells were engineered to hold oncolytic herpes simplex virus (oHSV), which specifically kills dividing cancer cells while avoiding normal cells.

The investigators first developed different BRAF wild type and mutant mouse models that more closely mimicked those seen in humans. As a result, they found that injecting patient-derived, brain-seeking melanoma cells into the carotid artery of the preclinical models results in the formation of metastatic tumors in the brain. This mimicked what is observed in patients with advanced melanoma cancer.

These injected cells express markers that enables them to pass the blood-brain barrier. They hold bioluminescent and fluorescent markers to help track them via imaging technologies.

Based on the investigators’ prior studies, which showed that different stem cell types are naturally attracted toward tumors in the brain, the investigators verified that stem cells injected in the brain would travel to multiple metastatic sites and not to tumor-free areas.

Following verification, the investigators injected stem cells loaded with oHSV into the carotid artery of mice with metastasis.

The results of the study showed that the oHSV-loaded stem cells significantly slowed tumor growth and increased survival compared with mouse models that received unaltered stem cells or control injections.

“Metastatic brain tumors—–often from lung, breast, or skin cancers––are the most commonly observed tumors within the brain and account for about 40% of advanced melanoma metastases,” said lead author Khalid Shah, MS, PhD. “Current therapeutic options for such patients are limited, particularly when there are many metastases. Our results are the first to provide insight into ways of targeting multiple brain metastatic deposits with stem cell-loaded oncolytic viruses that specifically kill dividing tumors cells.”

The investigators also developed an immunocompetent melanoma mouse model to examine the effect of both stem cell loaded oHSV and immune checkpoint blockers. The findings showed that the PD-L1 immune checkpoint blockade significantly improved the therapeutic efficacy of stem cell based oncolytic virotherapy in melanoma brain metastasis.

“We are currently developing similar animal models of brain metastasis from other cancer types as well as new oncolytic viruses that have the ability to specifically kill a wide variety of resistant tumor cells,” Shah said. “We are hopeful that our findings will overcome problems associated with current clinical procedures. This work will have direct implications for designing clinical trials using oncolytic viruses for metastatic tumors in the brain.”