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Scientists harness diptheria toxin and interleukin 2 to help the immune system attack melanoma
November 09, 2006Phase II trial continues
Prague, Czech Republic: Researchers investigating ways of prompting the immune system to recognise and kill tumour cells have found that a drug containing parts of the diptheria toxin appears to work well in patients with advanced melanoma (skin cancer).
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.\\\
European Organisation for Research and Treatment of Cancer
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.\\\
European Organisation for Research and Treatment of Cancer
Melanoma Current Events and Melanoma News RSSLaser therapy can aggravate skin cancer
High irradiances of low-level laser therapy (LLLT) should not be used over melanomas.
Quarter of a million children in England at risk of skin cancer from sunbeds
An estimated quarter of a million 11-17 year olds in England are being put at increased risk of developing malignant melanoma by using sunbeds, warn researchers in a letter to this week's BMJ.
Hundreds of genes distinguish patients likely to survive advanced melanoma
Although the chances of surviving advanced melanoma aren't very good with current therapies, some patients can live for years with cancer that has spread beyond the skin to other organs.
New Notre Dame study provides insights into the molecular basis of tumor cell behavior
A new study by a team of researchers led by Crislyn D'Souza-Schorey, associate professor of biological sciences at the University of Notre Dame, sheds light on the molecular basis by which tumor cells modulate their surroundings to favor cancer progression.
Switching immunosuppressants reduces cancer risk in kidney
Switching to a newer type of immunosuppressant drug may reduce the high rate of skin cancer after kidney transplantation, according to research being presented at the American Society of Nephrology's 42nd Annual Meeting and Scientific Exposition in San Diego, CA.
Cancer survivors may not be getting the help they need to stop smoking
More than a quarter of cancer survivors who still smoke have not been advised to quit smoking by their health care providers in the last year, according to a study published by researchers at Fox Chase Cancer Center in the current issue of the Journal of General Internal Medicine.
Melanoma treatment options 1 step closer
A targeted chemotherapy for the treatment of skin cancer is one step closer, after a team of University of Alberta researchers successfully synthesized a natural substance that shows exceptional potential to specifically treat this often fatal disease.
Resident physicians seldom trained in skin cancer examination
Many resident physicians are not trained in skin cancer examinations, nor have they ever observed or practiced the procedure.
New findings on the formation of body pigment
The skin's pigment cells can be formed from completely different cells than has hitherto been thought, a new study from the Swedish medical university Karolinska Institutet shows. The results, which are published in the journal Cell, also mean the discovery of a new kind of stem cell.
Studying cancer in pet dogs to find new treatments for human patients
A team of scientists at the National Cancer Institute (NCI) in Bethesda, USA, says that studying pet dogs with cancer could yield valuable information on how to diagnose and treat human cancers.
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