Using Herpesvirus to fight cancer

Cancer is an uncontrolled proliferation of cells that can either stay at the place of origin or metastasise to another part of the body. The out-of-control division of cells is due to faults in DNA, which can be triggered via an error in cell division, genetic mutations, inheritance or environmental factors and personal lifestyles.

The body’s immune system can often fail to recognise and attack cancer cells, in part due to the tumour making immune cells less active. T cells, a key part of our immune system, can be controlled by cancer through proteins known as checkpoint proteins – one example of this is the proteins PD-1 and PD-L1. One way to prevent this immune cell suppression is to interfere with PD-1/PD-L1 interaction, which allows our immune system to recognise and fight back against cancer cells.

Viruses commonly cause harmful diseases; however, they can also be modified genetically to use as agents to deliver therapeutic genes. “Oncolytic” viruses are a class of viruses that replicate selectively within tumour cells and kill them, leaving normal cells unharmed.

Over the past several decades, oncolytic viruses have generated considerable attention as cancer therapies, as they can directly kill cancer cells and be used to deliver other treatments that can be expressed locally in the tumour by modifying their viral DNA. This allows researchers to express high levels of drugs specifically within tumour cells, that would have otherwise caused side effects if given to the whole body. Examples of these kind of drugs include immunotherapies such as a protein that modifies the PD-L1 pathway, reactivating the immune system and helping the body fight back against cancer.

A recent study from the Seymour lab at the Department of Oncology has investigated the use of an oncolytic herpes virus-1. The team programmed this virus to express an antibody targeted against PD-L1. Once this virus infects a tumour cell, it replicates in the cell, eventually bursting the cell to infect and spread to neighbouring tumour cells. This capability to infect just tumour cells makes the programmed herpes virus the perfect vector to carry targeted immunotherapy drugs to assist with the destruction of cancer.

In this case, the team combined a PD-1/PD-L1 interference approach with an immunotherapy strategy to direct T cells towards PD-L1-expressing cells. They developed a bi-specific T cell engager (a.k.a BiTE) which causes an interaction between PD-L1 positive cells and T cells, prompting the T cells to kill the tumour cells. Once produced, this BiTE helps to kill large populations of PD-L1 positive cell types such as tumour cells and macrophages. The killing of these cell types and the presence of the virus combined turn the tumour from an immunologically “cold” tumour to a “hot” one – which means that the body’s immune system will start to notice the tumour and fight against it.

An example of the virus destroying tumour cell types can be seen below. In the second video, you can see the virus-encoded with PD-L1 BiTE, which allows T cells to kill tumour cells at a much faster rate.

Cancer cells being destroyed with just herpesvirus

Herpesvirus reprogrammed with BiTE

Caption: The death of cancer cells (black) by T cells (blue) with the virus and with the reprogrammed virus expressing PD-L1 BiTE. Tumour cell death can be seen in green and is much more rapid in the reprogrammed virus example.

The results of this study are very promising, and the next step for the team is to investigate the applications of oncolytic herpes viruses expressing PD-L1 BiTE in clinical trials.

About the study

This work was led by Postdoctoral Researcher Dr Hena Khalique, of the Seymour Lab. Prof Len Seymour heads the oncolytic virology lab at the Department of Oncology, University of Oxford. Their research aims to design and develop innovative anticancer viruses and cancer vaccines. Cancer Research UK funding supported this research.