Leukemia cells containing stained Epstein-Barr viruses

Virus vs. immune system: the link between viruses and cancer

19 September 2016

Dr John Nicholls (Croucher Senior Medical Research Fellowship 2009) has spent much of his career studying the role of the Epstein-Barr Virus, which causes Nasopharyngeal Carcinoma, one of the most common cancers in Hong Kong. After a life dedicated to finding a treatment for this usually terminal disease, Nicholls is seeing all his hard work culminate in a possible treatment.

Nasopharyngeal Carcinoma (NPC) affects the nasal cavity in adults, and Hong Kong has one of the highest incidence rates of the disease in the world. Causes can be hereditary, dietary, or due to lifestyle or infection by the Epstein-Barr Virus (EBV).

There appears to be a link between Hong Kongers’ diet of salted fish and vegetables and their vulnerability to EBV due to the genetics of the Southern Chinese. The disease is also known as the ‘Canton tumour’ because of its high prevalence in Southern China.

Nicholls was inclined towards pathology from an early age and finding the patterns that make disease diagnosis possible fascinated him.

“I’m a visual person, and pathology is very much a visual discipline, and it’s very intellectually stimulating,” says Nicholls, “You always have to know about diseases, there is always a new one coming along and I enjoy meeting that scientific challenge.” 

Dr Nicholls (right)

Nicholls trained in paediatric pathology in Australia and first came to Hong Kong in 1988. Here, he shifted his research focus to Nasopharyngeal Carcinoma (NPC), and started collaborating with researchers at the Queensland Institute of Medical Research (QIMR).

In Hong Kong, Nicholls has been involved in researching the interaction of viruses with cells in the human respiratory tract and his studies can be divided into two broad categories: acute infections such as influenza and respiratory viruses like MERS and SARS, and viruses that become oncogenic, modifying the host’s genome and eventually leading to tumours. The prototype is Epstein-Barr Virus (EBV), which is involved in the development of Nasopharyngeal Carcinoma (NPC).

Initially, he was working on NPC and conducting preliminary studies, but an avian influenza outbreak in Hong Kong, followed by other infectious diseases led him to pursue research in the field of emerging viral infections as well.

Viruses, avian influenza, and SARS

In 1997, during an outbreak of H5N1 avian influenza, Nicholls collaborated with other virus researchers in Hong Kong and abroad to investigate viral interactions with cells in the respiratory tract.

“I spent a lot of my time trying to find out why H5 was leading to such severe tissue damage. This involved looking at which cells were inflicting the changes, and the cytokines (a category of small proteins that are important in cell signalling, immune response, host response to infection, cancer, etc.) that were being produced by the cells infected by viruses,” explained Nicholls.

Things came to a head in late 2002 and early 2003 when unusual cases of pneumonia were reported in Guangdong, which rapidly spread to the rest of the world. Nicholls was part of a team that tested the patient samples from Guangdong and Vietnam for all known viruses; though at first their search came up dry.

But after the team successfully isolated cells affected by the virus that showed a cytopathic effect (structural changes in the host cell), Dr Nicholls was able to use electron microscopy to help identify a novel coronavirus.

H5N1 Avian influenza virus

But the threat of viruses and infectious diseases has continued. The continuous emergence of H5 viruses in the Southeast Asia region, pandemic swine flu in 2009, and Middle East respiratory syndrome (MERS) in 2012, prompted Dr Nicholls to work more closely with public health professionals over the years, studying cell receptors, cells infected by viruses, and tissue damage.

Growing infections

Most infectious diseases of the last few decades have crossed to humans through animals, but the animals themselves may not show clinical signs of the disease, which makes timely monitoring and surveillance of target animal species very important in the battle against viruses.

“I think the major challenge is to have a sense of awareness that these new viruses are out there,” says Nicholls, “one of the most crucial things is to have a good screening program.”

In 2006, Nicholls, together with his staff, established a lung and bronchial ex vivo (experiment conducted in or on tissues from an organism in an external environment) culture system to investigate the tropism and pathogenesis of emerging viral infections. Their large ex vivo system now has almost 300 lung and bronchial samples.

The World Health Organisation has now recognised the use of ex vivo cultures as a valid risk assessment, and this system can be used to see if new and emerging viruses in animal reservoirs can infect humans.

Nicholls also acknowledged the challenges around developing vaccines, as viruses are constantly emerging and evolving.

Vaccination is arguably the best way to protect and cover the largest portion of a population, but because the various forms of influenza affect humans sporadically and do not always easily transmit from one person to another, it’s not cost effective to develop vaccines for some forms of the virus.

Viruses and cancer

In addition to his work on influenza and other respiratory viruses, Nicholls also studies the Epstein-Barr virus (EBV) and its connections to cancer.

The link between EBV, one of the eight known viruses in the Herpes family and NPC was made back in the 1970s and since then the role of EPV in causing tumours has intrigued researchers.

“When I first came to Hong Kong I was looking at how the virus was affecting and causing tumours. We have worked very closely with researchers from QIMR, who had been working on vaccines, trying to prevent NPC,” recalled Nicholls, who is now a Clinical Professor of Pathology at the University of Hong Kong.

Nicholls and his team found that patients with NPC could train their body’s immune systems to fight off cancer. This is because when a person develops NPC and the virus is found within tumour cells, treatment measures will only target the tumour cells and leave the normal ones alone.

Nicholls, together with other researchers in Queensland, have developed a novel T-cell based immunotherapy procedure. Already having completed Phase I trials on third and fourth stage cancer patients, the treatment involves stimulating the patient’s T-cells to proliferate and attack virus-infected cells, while leaving other cells alone.

Blood from these patients was sent to Queensland, where T-cells were stimulated and then sent back to Hong Kong reinsert into the patients. The objective of the study was just to see if the procedure was safe, and it was found that there were no adverse side effects, but intriguingly the therapy already seemed to prolong survival of established NPC patients.

During the trial monitoring, it was found that the group that received T-cells seemed to live longer than those who didn’t, indicating that there may be clinical benefit of the therapy.

“Phase I wasn’t necessarily about survival but more about safety. But based on this successful finding, we are now embarking on Phase II, which is larger, with many more patients and aims to see if the therapy actually works,” explained Nicholls.

Phase II study started earlier this year with the continued collaboration between the Department of Clinical Oncology at HKU and QIMR. Although the results are not yet known, Nicholls is optimistic that the therapy can be a treatment for NPC if both phases are successful.

“This will probably not replace current treatment of NPC at late stages as you can still get about 5 years of survival with it,” said Nicholls. “But we anticipate that this therapy will be something that will be combined with existing therapy. This can be something we’ll use to improve patient survival.”

Dr Nicholls attended the University of Adelaide, South Australia from 1977 to 1983 and obtained postgraduate training in Pathology at the Institute of Medical and Veterinary Sciences at the Queen Elizabeth Hospital and Adelaide Children’s Hospital. Following his move to Hong Kong in 1988, he was a lecturer of Pathology at the University of Hong Kong and is currently an Associate Professor. He was a key member of the research team at the University of Hong Kong that successfully isolated the novel coronavirus SARS in 2003. He was awarded the Croucher Senior Medical Research Fellowship in 2009 to work on novel therapeutic strategies for influenza.  

To view Nicholls’ personal Croucher profile, please click here.