Peter Mac cancer therapy shows high promise

Scientists at Melbourne's Peter MacCallum Cancer Research Centre have demonstrated an ingenious strategy for boosting and focusing the body's immune defences that causes dramatic regression of tumours in mice.

Peter Mac's NHMRC-funded immunology program, headed by Dr Joe Trapani and Dr Mark Smyth, made national headlines with its advance this week, but Trapani said the technique was at least two years from human trials. "We're conscious of the need to keep a lid on people's expectations," he said.

Ultimately, he said, it was hoped the novel therapy would be used mainly to prevent or treat secondary cancers spawned by residual cancerous cells after surgery, chemotherapy or radiation therapy.

Trapani said his team had been developing the technique for more than a decade. Unlike many experimental immunotherapy strategies, it exploits cytotoxic T-cells to attack tumours, instead of antibody-secreting B-cells.

Smyth, Trapani and senior researchers Michael Kershaw and Phil Darcy have devised an ingenious technique that equips T-cells with an antibody-like targeting system programmed to recognise specific antigens over-expressed by cancerous cells.

The technique involves introducing a chimeric gene into T-cells extracted from the patient's blood. Trapani said the transgene specifies a receptor-like protein on the T-cell's surface. The external domain forms a single-chain antibody, linked to two intracellular signalling domains engineered in tandem.

When the antibody-like receptor binds to a cancerous cell, both signalling domains are activated simultaneously.

One signalling domain activates the T-cell's inherent capacity to kill cancer cells. It secretes perforin, a pore-forming protein that punctures the cancer cell's outer membrane. The T-cell then secretes granzymes (serine proteases) through the pores, inducing apoptosis, or programmed cell suicide.

The second signalling domain causes the T-cell to begin secreting cytokines -- cell-activating compounds like gamma interferon that stimulate the immune system to produce an inflammatory response that also attacks the cancer.

The first wave of gene-modified T-cells initiates a positive feedback loop that results in an overwhelming cytotoxic response that destroys the tumour.

Trapani said the chimeric receptor was the key to the technique's success.

In early experiments, the Peter Mac team found the antibody-like targeting mechanism was not sufficient to destroy the tumour, because sub-optimal signalling to the T-cells meant that the transfused T-cells did not proliferate, and did not persist after encountering cancer cells. The team then conceived the idea of using dual T-cell signalling motifs in tandem to augment the T-cell response.

"We found that, both in vitro and in vivo, the strategy provides a powerful stimulus for killing cancerous cells," Trapani said. "Once engaged, the T-cells produce large quantities of cytokines, and acquire the ability to proliferate."

Trapani said the T-cells were engineered to express single-chain antibodies targeted to antigens commonly over-expressed by tumours. They include Erb-B2, the receptor targeted by Herceptin, the monoclonal antibody therapeutic for breast cancer, and carcinoembryonic antigen (CEA).

A possible hitch in the strategy, Trapani said, was that the single-chain antibodies used in the mouse experiments cannot be used in humans, because the human immune system would recognise them as alien and produce neutralising antibodies that would render them ineffective. The receptors used in human trials would have to be modified in structure to make them invisible to the human immune system.

The beauty of the technique, Trapani said, was that because growth factor receptors are involved in the rapid growth of cancers, the cancerous cells cannot "escape" the therapy by dispensing with the receptors.

The transgenic T-cells could also be used to treat a range of cancers -- Erb-B2, for example, is over-expressed in a proportion of breast adenocarcinomas, but is also found in some cancers originating in gastrointestinal and other malignancies.

"When we begin recruiting human volunteers for clinical trials in two or three years' time, we hope to recruit on the basis that patients will share specific antigens, even though their cancers may involve different organs," Trapani said.