Scientists Harness Diptheria Toxin And Interleukin 2 To Help The Immune System Attack Melanoma

In the first part of a phase II clinical trial to test the drug denileukin diftitox (also known as DAB(389)IL2 or ONTAK) in melanoma, five out of seven patients with stage IV disease experienced significant regression or stabilisation of both tumours and metastases. The two other patients in whom the disease progressed were on a lower dose of the drug. All the patients are still alive after 12 months.

Dr Jason Chesney, associate director for translational research at the JG Brown Cancer Center, University of Louisville, Kentucky, USA, told a news briefing at the EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Prague today (Thursday 9 November): "We are seeing some exciting results in stage IV melanoma patients whose median life expectancy is normally only about eight months. The phase II trial is continuing to examine the efficacy of denileukin diftitox in patients with melanoma."

The immune system that attacks cancer cells in humans depends on a balance between T cells, which specifically recognise and attack antigens such as tumour cells, and suppressive or regulatory T cells (Tregs), which turn off activated immune cells in order to prevent autoimmunity.

Dr Chesney explained: "Recently a subset of regulatory T cells has been found to directly suppress the activation of the anti-tumour T cells, but it was also discovered that, if the Tregs were depleted by targeting them with denileukin diftitox, then particular T cells in the immune system known as CD8+ T lymphocytes were able to attack and kill the melanoma cells in mice."

Denileukin diftitox is a fusion protein made up of amino acid sequences for the diptheria toxin and the T cell growth factor, interleukin 2 (IL2). It targets Tregs that have IL2 receptors on their cell surface, and it binds to part of the receptor called CD25. Once it reaches the inside of the cell it prevents protein synthesis, which leads to cell death within hours.

"We thought that if denileukin diftitox could selectively deplete Tregs in patients with melanoma, this would allow the CD8+ T cells to do their job of recognising and attacking the melanoma cells," said Dr Chesney.

Dr Chesney and his colleagues gave seven patients with stage IV melanoma nine or twelve micrograms per kilogram of body weight daily for four days, every three weeks for four cycles. The two patients on the lower dose had newly detectable tumours and tumour growth after two cycles. However, the five patients on the higher dose experienced significant regression of several metastatic tumours after four cycles, including subcutaneous tumours and metastases in the liver and lymph nodes.

One patient had two tumours on the leg that had died and became infected, requiring surgery. When the researchers examined the tumour tissue they found that it was surrounded by CD8+ T lymphocytes. "This meant that the lymphocytes had been successfully activated to attack the tumour, which consequently had died. We also found that the concentration of Tregs in this patient decreased by more than a half after the second day's dose of denileukin diftitox," said Dr Chesney.

"To our knowledge, this is the only trial to study the effects of Treg depletion in human cancer patients. From the results, we conclude that depleting Treg cells in patients with melanoma may allow the immune system to be activated successfully to kill cancer cells. These patients have survived longer than the median average life expectancy of a patient with stage IV melanoma.

"We also believe that, in the future, immunotherapies that depend on depleting Treg cells may prove to be useful in all types of cancer."