Vaccines are not new. Well, not vaccines that anticipate when we will get an infection and prime our body’s immune system to beat it. But a new era of vaccines is emerging armed to fight genetically sophisticated diseases like cancer and HIV after they occur. The ANU laboratory of Christopher Parish is leading the way.

Around 30 years ago, an idea about an unconventional way to use the body’s immune system to attack disease began taking shape in the mind and laboratory of Professor Christopher Parish.

So out of the ordinary was this idea that a pharmaceutical company would reject it at the time as too left field. “We don’t need a new way,” they would say, still buoyed by the successes of recent vaccine developments that prevented polio, whooping cough and smallpox.

Little did the company know that the premise they rejected would lead to a new way of approaching vaccines for combating infectious diseases that have emerged since, as well as cancer.

This leap forward is thanks to the long, laborious work of discovery by Parish and his team in the Cancer and Vascular Biology Group at The John Curtin School of Medical Research (JCSMR).

Parish came to JCSMR in 1969 to continue to work alongside immunologist Professor Gordon Ada, who had supervised his PhD at the Walter and Eliza Hall Institute in Melbourne. He joined the medical research school at a time when Ada and virologist Professor Frank Fenner were at the height of discovery in their respective fields and raising the international reputation of JCSMR.

He very nearly didn’t take this path. He had studied a generalist agricultural science degree in Melbourne, and taken the PhD in immunology because it was available at the time and he had enjoyed the little immunology he had done as an undergraduate.
But the environment at JCSMR set him firmly down the path of immunology, which would see him follow in the footsteps of these eminent scientists and make inroads into an emerging area of the field: therapeutic immunology.

All the vaccines currently in use against bacterial and viral infections are prophylactic: that is, they anticipate infection. By injecting parts of pathogens into the body, the immune system is trained to recognise the infection and fight it when it occurs. This method dates back to the late 18th century when Edward Jenner, the ‘father’ of vaccination, attempted to vaccinate against smallpox using cowpox.

Parish’s work has focused on therapeutic vaccines, around which a large field of research has recently sprung up. These types of vaccines harness T-cells, not just antibodies, and are administered to treat a disease once it has occurred.

Because of the complexities of this approach, the development of such treatments is “problematic”, according to Parish. There are currently no therapeutic vaccines in use, but researchers hold great hope for their potential to fight the “incredibly genetically unstable” diseases of the 21st century including HIV, cancer and influenza.

“Most of the easy vaccines have been developed: smallpox, measles, and polio – all of the injections you get when you’re young are about training your immune system to remember and recognise bacterial and viral infections as impostors and fight them. The new vaccine for cervical cancer targeting human pampilloma virus is also like this.

“The next frontier is therapeutic vaccines, but they’re much more tricky and technical than prophylactic vaccines. There are hundreds under development in labs around the world, but none are routinely used in patients.”
As Parish investigated T-cell immunity further in these early days his research began to split into two paths as his detailed molecular studies provided insight into the mechanics of vascular science, or the blood vessel system.

“I was looking at how cells of the immune system cross blood vessel walls and enter tissues. As we investigated this, it became clear we could apply this to other areas and, in particular, cancer,” Parish says.

It became a focus of Parish’s research to harness aspects of the vascular system in the fight against cancer and one that has led to a successful collaboration with a pharmaceutical company now developing a drug based on Parish’s enquiry.
The drug, called PI-88, utilises a two-pronged approach to halt the growth and spread of solid cancers.

Firstly, there is the prevention of cancer cells escaping into the blood stream from the main tumour that could potentially cause a secondary tumour, or metastasis.

Parish and his team have developed a sugar molecule that inhibits the enzyme heparanase that causes the breakdown of the basement membrane lining blood vessels, which may allow cancerous cells to enter the blood stream as well as escape from circulation and enter distant organs.

The second part of PI-88’s actions is the inhibition of the process of angiogenisis – the formation of new blood vessels to the tumour – that feeds the tumour and helps it to grow.

“Cancer tissue is like any tissue in the human body. It needs a blood supply to thrive. Tumours establish blood vessels that provide them with nutrients to grow and get larger. By blocking the development of a blood supply by the tumour, we’re ensuring that the tumour doesn’t get any larger.”

As this approach began to show promise, biotech company Progen Pharmaceuticals recognised the potential of the research. Since 1993, when a commercialisation agreement negotiated between Progen and ANU over two years was put in place, PI-88 has been going through the long, detailed proof and production process, with encouraging results.

The first phase of human trials of PI-88 was conducted in 1999 and since then a number of trials on different types of cancer have taken place. A phase 3 trial of PI-88 in patients who have had their cancer surgically removed from the liver is due to begin in late 2007.
Results from the most recent phase 2 trial in these patients provide an insight into the effect of PI-88. Treatment with the drug increased the time of recurrence of the disease by approximately 28 percent from 27 to 48 weeks.

The results are promising, but the development of a new drug is a long and involved process and can take years of getting the dosages right, identifying the best patient group to treat, demonstrating efficacy and applying for registration. PI-88 may still not be available for a handful of years – although Parish, along with cancer sufferers around the world, is hopeful that it will successfully come to market sooner rather than later.
Much of the development of PI-88 now lies with Progen, who Parish says has been a good fit for PI-88 and as a commercialisation partner with ANU. Parish has turned his research beyond PI-88 to devising a way to arm the immune system to, as he says, “finish off” tumours.

In alliance with the laboratory of Dr Joseph Altin from the School of Biochemistry and Molecular Biology in the ANU College of Science, this is another research project that is currently being tested and developed in the form of a cancer vaccine, called Lipovaxin.
Lipovaxin uses the immune system approach to cancer treatment. It essentially arms dendritic cells – which are crucial to mobilising a T-cell immune response to infections – to activate an attack against the tumour cells.

Lipovaxin primes the dendritic cells with a cancer antigen, and they present this antigen to the killer T-cells and other T-cell types. This activates them to seek out the tumour cells in the body. They invade the tumour cells and either kill the tumour cells by direct cell contact or recruit in other white cells, such as eosinophils, that explode, killing the cancer cells and those around them. Early tests in mice have shown that the cancer can almost be completely destroyed using this approach.

Cancer immunotherapy is a therapeutic technique which is already being experimentally used on patients in cancer treatment centres, mostly overseas. The current approach requires dendritic cells to be taken from the body, primed with antigen and grown in culture over days in a lab, and then reinjected back into the body.

In comparison, Lipovaxin is injected into the patient as a first step, priming the dendritic cells inside the body to mobilise the immune system to attack the tumour.

“We envisage this vaccine would be administered after initial treatments and finish the cancer off,” Parish says. “What’s very exciting about it is that it can be ‘modified’ to induce immunity against many different cancer types.”

Lipovaxin – which is being commercially developed by biotechnology company Lipotek – will this year begin phase one human trials in Australian melanoma patients.

Although it might seem that Parish has the quest for a cancer vaccine all wrapped up, he’s not jetting off into the sunset with novel in hand and sunshade in luggage just yet.
Another aspect of the tumour environment he and his team are currently tackling with a therapeutic approach in mind is the role of platelets in tumour growth and metastasis. “It seems as if, to put it simply, the platelets are recruited by some tumours to help them become invasive quite quickly,” Parish says. “Blocking platelet cell and tumour cell interaction may also have therapeutic potential.”

We can only hope. But given Parish’s history for finding his way from a small idea to big potential for cancer treatment that could benefit millions of people, perhaps such hope is well-founded.

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ANU Reporter 
Winter 2007