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 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.

Local/regional recombinant interleukin 2 (rIL-2) immunotherapy of tumors. Intra-arterial continuous infusion of rIL-2 in bladder cancer patients: a phase I study.

We have investigated clinical and immunological effects of two 5-day cycle continuous infusion of four escalating doses (3,000; 30,000; 300,000; 3,000,000 U/m2/day) of intra-arterial (i.a.) rIL-2, in ten patients with superficial (Ta-T1, N0, M0) bladder TCC. Tumor TUR was performed four days after the end of the second IL-2 cycle. No clinical or laboratory toxicity was detected in any but one patient, who developed grade III hypotension and grade III neurological toxicity. Two CR and two PR were observed in patients treated with 30,000 and 300,000 U/m2/day of rIL-2, respectively. Clinical responses lasted 8+, 8+, 4+ and 4+ months, respectively. Two out of ten patients developed recurrences two months after tumor resection. In the peripheral blood, no changes in the percentage of T (CD3+) lymphocytes were observed, while a significant increase of CD3+ CD16+ T cells was found in 6/9 patients. In contrast, NK (CD3- CD16+) cells were augmented only in 2/9 patients. An increase of B lymphocytes (CD19+ cells) and monocytes (CD14+ cells) was also observed in 3/9 and 7/9 patients, respectively. Lymphocyte activation marker expression (CD25, CD71, HLA-DR) increased mainly on T lymphocytes. NK and LAK activities were enhanced in 4/10 patients, while ADCC activity augmented in 2/10 patients. No detectable increased levels of plasmatic lymphokines (gamma-IFN and alpha-TNF) were found. Enhanced CD8+ and CD4+ tumor infiltrating lymphocytes were demonstrated after IL-2 treatment. Moreover, at the tumor site, lymphocytes expressing CD25 and HLA-DR antigens were noted. Tumor infiltrating macrophages were positive for IL-1 alpha, IL-1 beta and alpha-TNF.