A friend on the inside

Cancer is a formidable foe. It has a number of sophisticated strategies for evading the immune system, mostly based on making itself look like it belongs – that it is ‘self’. But cancer’s days of flying under the immune system’s radar may be coming to a close, thanks to huge advances in the science of immunology.

Professor Derek Hart and Professor Joy Ho (MBBS ’88) both started their careers as haematologists, becoming specialists in the study of blood and  blood diseases. Blood plays a big role in transporting the soldiers of the immune system, called T cells, around the body, so haematologists become very familiar with the immune system’s architecture. Through this, Professors Ho and Hart number among the leaders in their field, both with a strong immunological skill set.

They are also each participating in world-leading but quite different research into how the immune system can be coaxed into recognising cancers as the threat they are.

“The field is very exciting because it’s a totally new mode of treatment,” Professor Ho says. “Now we’re trying to develop clinical  techniques that allow new immune therapies to be applied to patients.”

Part of the promise of immune therapies is that treating cancer may become less of an ordeal. Rather than trying to irradiate, poison or cut out the cancer – with all the collateral traumas that brings – the cancer is tackled on a cellular level as part of the natural immune processes. This is an immunology Holy Grail that is coming into reach after decades of work.

As a teenager, Professor Hart set up a lab for himself at home where he eagerly pursued  his innate interest in science. His career has seen him leading research teams around the world, including in his current role with the Dendritic Cell Research Group which  has highly skilled, multidisciplinary staff based at Concord, Westmead and Royal Prince Alfred Hospitals.

As the group’s name suggests, the focus of the team is on dendritic cells, which were first found in mouse tissue through the Nobel Prize-winning work of Canadian immunologist Ralph Steinman. But Professor Hart himself was the first to identify them in rat and human organs.

“I looked down  the microscope, and dendritic cells stared back at me,” says Professor Hart, who has bright personal energy and an easy laugh. “Gee whiz what am I looking at? I didn’t have a clue. Then I realised they were probably related to Steinman’s cells.”

Dendritic cells have the job of raising the alarm when an infection invades the body. They also ‘describe’ the infection to the immune system using antibodies, so the system can produce T cells (the ‘T’ stands for thymus, the organ in which the cells mature), armed to fight that specific enemy.

Though researchers avoid overpromising, there is the whispered possibility in the immunology community that dendritic cell manipulation could one day lead to an anti-cancer vaccine.

Right now though, the key task for Professor Hart’s team is to create antibodies to treat cancers using some of the target molecules they’ve identified. They are also developing methods to purify and manipulate dendritic cells for treating cancer. Ultimately, the cells would  be injected into a patient to stimulate anti-cancer action in the immune system. This is a hugely detailed and painstaking process. But ask Professor Hart what is the toughest nut to crack and he’ll say finding the funding his team needs to take the next steps.

“The real buzz from day one was getting to the point where we are now, where we can make products that could actually have a real impact on patient care,” he says. “But we need funding to get under way with the clinical trials of those products.”

For her part, Professor Ho is highly aware of the constraints of the trial process. Where Professor Hart is mainly a pure scientist, Professor Ho is part of a laboratory research team and  a principal investigator in clinical trials.

Professor Ho’s skills were recognised early with a Young Researcher of the Year Award in 2001. Since then she has taken leading research roles, finding a particular fascination with myeloma, a cancer of the bone marrow. Somehow, through all her years of intensive research, she’s also found time to become proficient in French, which she uses during visits to New Caledonia, where she’s part of a team that conducts clinics  for local people with haematological malignancies.

A big focus for her now is running clinical  trials. With a warm intelligence, she describes each trial as like putting together a jigsaw puzzle. A key piece is finding the right research question that will bring maximum benefit to patients. Other pieces include enrolling the appropriate patients and, of course, funding.

Professor Ho’s research team works in a complex of rooms just beyond the grand, sandstone entry doors of Royal Prince Alfred Hospital. To reach her office, you walk through the waiting room where patients with cancers such as leukaemia, lymphoma and myeloma are waiting for their next or even first appointment in a clinical trial of a new therapy.

Where Professor Hart has a focus on dendritic cells, Professor Ho and her team are fascinated by the possibilities of directly convincing T cells to fight cancers.

The starting point is to manipulate the T cells through genetic engineering. A blood sample is taken from the patient and the T cells are extracted. The sample is then sent to the United States, where a virus is used to introduce a receptor and other elements into the T cell that will direct it to the cancer. This turns the T cell into what’s called a chimeric antigen receptor T cell, or CAR-T cell for short.

While this is happening, the patient undergoes chemotherapy in Australia to deplete their lymphocytes, so the engineered CAR-T cells can be injected and begin attacking the cancer.

As the media is trumpeting the admittedly impressive results of CAR-T trials overseas, Professor Ho knows there’s a good case for caution. It’s widely known  in the research community that for some people, the new therapies may not be effective or may lose effectiveness.

More than that, some patients have been seriously affected by cytokine release syndrome due to the release of chemical agents when the CAR-T cells are applied, a process that is not yet fully understood. Patients have been made sick by some therapies and  there have been deaths.

“Safety is a paramount concern,” says Professor Ho. “These are new therapies and you have to be able to pick up the nuances of every reaction and  side effect. We are very well set up to do that here.”

RPA is one of only two sites in Australia doing CAR-T cell therapy, and while the US gets much of the immunology limelight, the RPA research team has made the best of its relatively meagre resources over the years to be recognised as world leaders in haematology and immunology.

As Professor Hart and Professor Ho explore different regions of the immunology landscape, their growing collaborations hold considerable promise. The two researchers also share the same core inspiration for their work. “I did medicine to help people,” Professor Ho says. “I get great joy out of being able to provide them with excellent therapy.”

Professor Hart and Professor Ho are part of the University’s Cancer Research Network, which brings together some of the brightest minds of the University and its affiliates.

To support the research work of Professor Hart and Professor Ho, to help more clinical trials happen, or for more information about the advances in immunology, please contact David Meredith on +612 8627 0797 or david.meredith@sydney.edu.au.

Written by George Dodd
Photography by Matthew Vasilescu