New trials planned for Melbourne team's cancer vaccine

It began as a routine trial of a therapeutic vaccine for melanoma, but it had a spectacular and unexpected outcome -- all but two of the 19 patients treated with the vaccine are still alive two years after beginning treatment.

In this week's Proceedings of the National Academy of Science, Assoc Prof Jonathon Cebon's research team at the Ludwig Institute for Cancer Research and the Austin and Repatriation Hospital in Melbourne described what may prove to be a potent new therapy for the deadliest form of skin cancer.

The study also involved researchers at the Peter MacCallum Cancer Centre in Melbourne, and biotechnology company CSL (ASX:CSL).

If the results of the Phase I trial hold up in a new trial in 100 melanoma patients, it could be very good news for around 50 per cent of melanoma patients who have undergone surgery to remove secondary tumours.

Cebon said an observant colleague noticed that the survival rate of patients treated with an antigen-adjuvant combination after surgery for melanoma tumours seemed much higher than in a control group, or in a third group treated with the antigen alone.

The double-blind, placebo-controlled trial sought to determine if the vaccine would elicit a strong, combined immune response -- which it did, when the results were unblinded.

But Cebon's colleague noted that the patients who survived were those who exhibited the strongest immune response, after treatment with the prototype vaccine.

Where many modern vaccines contain peptide antigens, the Ludwig vaccine comprises a single, intact protein, NY-ESO-1, mixed with the CSL proprietary Iscomatrix adjuvant.

Cebon said the vaccine was trialled on the basis of anecdotal accounts suggesting that cancer patients who mounted a natural immune response to NY-ESO-1 had extended survival.

Cebon said that, in addition to occurring in about 50 per cent of melanoma tumours, it was also expressed in about 50 per cent of head, neck, lung, bladder and liver cancers. If it proves effective against melanoma tumours, the vaccine should also work against other tumours expressing NY-ESO-1.

The key to the vaccine's potency appears to be CSL's Iscomatrix adjuvant, Cebon said. The adjuvant, a cocktail of a phospholpid, cholesterol and saponins, forms 40-nanometre microspheres that encapsulate the antigen for presentation to the immune system.

All the patients involved in the trial had undergone surgery to remove metastatic secondary melanoma tumours from lymph nodes, or from major organs including the brain and lungs.

All patients were at high risk of relapse -- 70 per cent for patients with lymph-node tumours, and almost 100 per cent within 12 months for patients with tumours in major organs.

Patients received three intramuscular injections, one month apart. Cebon said that those who received the antigen alone exhibited only a feeble immune response, and experienced a relapse rate similar to the control group.

At the maximum dose employed in the phase 1 trial, the combined vaccine proved to be a potent activator of CD-8 cytotoxic T-cells, the immune system's principal defence against cancerous cells. It also activated CD-4 'helper-inducer' T-cells and antibody-secreting B-cells.

"We didn't design the trial as a randomised, prospective study," Cebon said. "The trial didn't have the statistical power to give us confidence that the high survival rate in the test group is real, but taken in context with the immunological data, it warrants another, randomised trial next year."

The new, multi-centre trial will involve 100 patients. It will include sites in all Australian states, and several sites in the UK. It would be designed to produce a definitive result that could see the vaccine proceed into Phase III trials and eventual clinical use.

Cebon said NY-ESO-1 was an ideal therapeutic target for cancer, because it was highly immunogenic -- a consequence of the fact that it is expressed only in early embryonic development, and not in adult somatic tissue. The immune system recognises it as an alien antigen, and mounts a natural response against cells expressing it.

While stem cells express NY-ESO-1, they are invisible to cytotoxic T-cell attack because they do not express Class 1 MHC antigens. The fact that many different cancer types express NY-ESO-1 also makes it a promising target for a generic cancer vaccine.