Local activation of immune response in bladder cancer patients treated with intraarterial infusion of recombinant interleukin-2.

Tumor regression induced in cancer patients by i.v. infusion of interleukin-2 (IL-2) is often accompanied by severe side effects. To investigate whether local administration would affect immune response without the side effects, two 5-day cycles of continuous intraarterial [internal iliac artery] infusion of recombinant interleukin-2 (rIL-2) were performed in 12 patients with transitional cell carcinoma (tumor stage 1, node stage 0, metastasis stage 0, and grade 1-2) of the bladder. Four groups of 3 patients were treated at each of 4 escalating doses of rIL-2 (18 x 10(3), 18 x 10(4), 18 x 10(5), and 18 x 10(6) IU/m2/day) throughout the course of the two IL-2 cycles. This treatment was effective in inducing a marked intratumor inflammatory response, consisting mainly of T-lymphocytes and macrophages. A remarkable dose-dependent increase in the levels of soluble CD25 was observed in the urine of all patients, which was associated constantly with an enhanced number of intratumor CD25+ cells. Intratumor macrophages were often immunoreactive for interleukin-1 and/or tumor necrosis factor, suggesting an activated status. Increased levels of soluble CD25 and CD25+ lymphocytes were observed in peripheral blood only at the two highest doses of rIL-2, while increased percentages of circulating HLA-DR+ and CD71+ lymphoid cells and enhancement of CD3+/CD16+ T-lymphocytes were found at lower doses. Peripheral blood eosinophils were augmented in almost all patients but were rarely increased in situ. We provide evidence that continuous intraarterial infusion of rIL-2 activates host immune response, acting preferentially at the tissue level.

Continuous intra-arterial administration of recombinant interleukin-2 in low-stage bladder cancer. A phase IB study.

Toxicity and clinical effects of intra-arterial (IA) continuous infusion of recombinant interleukin-2 (rIL-2) were evaluated in twelve patients with low-stage transitional cell carcinoma (TCC) of the bladder (T1NOMO; G1 to G2). rIL-2 dosages were escalated from 18 x 10(3) to 18 x 10(6) IU/m2/d in four groups of three patients. After two 5-day courses, separated by a 48-hour interval, evaluation of clinical response and transurethral resection (TUR) were carried out. World Health Organization (WHO) Grade 3 toxicity occurred in 2 of 12 patients (hypotension/mental confusion and fever, respectively); all side effects rapidly disappeared after infusion was abandoned. No laboratory toxicity developed in any patient. Two pathologically proven complete responses (CR) were achieved using 18 x 10(4) IU/m2/d, and three partial responses (PR) were achieved using 18 x 10(5) IU/m2/d in two patients and 18 x 10(6) IU/m2/d in one patient, giving an overall response rate of 42%. All objective responses are still ongoing after a mean follow-up time of 23 months (range, 12 to 32 months). Local relapses occurred 3 months after TUR only in two nonresponders.

Local immunotherapy of superficial bladder cancer by intravesical instillation of recombinant interleukin-2.

Local immunotherapy of superficial bladder cancer by endovesical administration of recombinant interleukin-2 (rIL-2) was investigated in a phase I-II study. Twenty-five patients with Ta-T1, N0, M0, G1-G2 transitional cell carcinoma of the bladder received an induction course of rIL-2 (10 daily instillations) with the tumor in place using an interpatient dose escalation scheme from 3 to 18 x 10(6) IU/day. Seven to fourteen days after the end of the induction course, the objective clinical response was evaluated and transurethral resection of the bladder tumor was carried out. Four maintenance courses (10 daily instillations) were started 1 month after surgery and carried out every 4 months at a dose of 6 x 10(6) IU/day in all patients. Follow-up visits were scheduled bimonthly during treatment and then every 6 months. No evidence of laboratory, local or systemic toxicity was observed even at the highest rIL-2 dosages. Induction of a local inflammatory response could be demonstrated at the tumor site after intravesical rIL-2 treatment. The significant reduction in tumor diameters observed in some patients may be interpreted as a sign of the biological activity of this rIL-2 regimen. Further exploratory work is required to evaluate the clinical efficacy of this immunotherapeutic approach.