PRAGUE, Czech RepublicFive of seven advanced melanoma patients had significant regression or stabilization of disease after treatment with Ontak (denileukin diftitox, Eisai), US researchers reported at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (abstract 264). All the patients remained alive after 12 months. "We are seeing some exciting results in stage IV melanoma patients whose median life expectancy is normally only about 8 months," said Jason A. Chesney, MD, PhD, assistant professor of medicine at the University of Louisville's James Graham Brown Cancer Center, who spoke at a press briefing.
Ontak is a recombinant DNA-derived cytotoxic protein composed of the amino acid sequences for diphtheria toxin fragments A and B followed by the sequences for interleukin-2. It is designed to carry the cytocidal diphtheria toxin to cells that express the IL-2 receptor on their surfaces. The drug binds to the CD25 segment of the receptor; once the toxin fragments enter the cell, death occurs within hours. The FDA approved Ontak as an orphan drug in February 1999 for treatment of cutaneous T-cell lymphoma.
The immune system's response to cancer depends on a balance between T cells that specifically recognize and attack antigens on tumor cells and suppressive or regulatory T cells (Tregs) that turn off the activated immune cells to prevent autoimmunity. "Recently, a subset of regulatory T cells [CD4+CD25high Tregs] has been found to directly suppress the activation of antitumor cells," Dr. Chesney said. "But it was also discovered that, if the Tregs were depleted by targeting them with denileukin diftitox, then CD8+ T lymphocytes were able to attack and kill the melanoma cells in mice."
Dr. Chesney and his colleagues hypothesized that denileukin diftitox could selectively deplete Tregs in melanoma patients and enable the patients' CD8+ T cells to recognize and attack their cancer cells. The team enrolled the seven patients and assigned two to receive 9 μg/kg of the drug and five to get 12 μg/kg for 4 days every 3 weeks for four cycles.
After two cycles, the two patients given the lower dose had newly detected tumors and tumor growth. However, the five patients treated at 12 μg/kg experienced significant regression of several metastatic tumors after four cycles, including subcutaneous tumors and metastases in the liver and lymph nodes.
One patient had two dead tumors on the leg that had become infected and required surgery. On examination, the researchers found that the tumor tissue was surrounded by CD8+ T lymphocytes. "This meant that the lymphocytes had been successfully activated to attack the tumor, which consequently had died," Dr. Chesney said. The researchers also found that the concentration of Tregs in this patient decreased by more than 50% after the second dose of denileukin diftitox.