Local continuous high dose interleukin 2: a new therapeutic model for the treatment of advanced bladder carcinoma

Because efficient i.v. administration of interleukin 2 (IL-2) in tumor patients leads to severe cardiopulmonary side effects, we developed a new form of IL-2 application that allows activation of all IL-2-responsive immune cells directly at the tumor site. In five patients with T4N0M0 transitional cell carcinoma of the bladder, we used high-dose, continuous IL-2 perfusion of the bladder (1000 units/ml, 2 ml/min, 24 h/day), for 5 days after incomplete transurethral resection of the tumor. The total dose, 15 million units, was repeated after 4-12 weeks. None of our patients showed any evidence of side effects. In blood and especially in urine, the number of eosinophil leukocytes was remarkably increased. Eosinophils were attached to the tumor cells and degranulated on them. Before treatment, no cells positive for IL-2 receptors were found in urine, and only 0-3% of lymphocytes positive for IL-2 receptors were detected in blood. After the first cycle and especially after the second, a distinct increase in positive cells up to 17% occurred. One patient had a complete histologically confirmed remission and is free of tumor 6 months after therapy. Another patient died of a vertebral metastasis 8 weeks after the first (and only) therapeutic cycle. Local administration of a high dose of IL-2 induces local and systemic immunopotentiation diagnosed by activation marker analysis without any side effects and can be used in inoperable transitional cell carcinoma of the bladder. The optimal dosage still needs to be defined. Bladder carcinoma is an ideal model that offers a unique chance to use urine cytology to study the cooperation and activation of immune cells at the tumor site.