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Local Activation of Immune Response in Bladder Cancer Patients Treated with Intraarterial Infusion of Recombinant Interleukin-2¹

Departments of Experimental Medicine [F. V., A. P., S. M., M. P., L. F., A. S.]; and Biopathology, University "La Sapienza," Viale Regina Elena 324, Rome 00161 [A. S., L. R., C. D. B.]; Urologic Clinic, Department of Surgery, L'Aquila University, Viale della Croce Rossa, L'Aquila 67100, Italy [A. T., T. N., P. C. B., L. M.]; and EuroCetus B. V., Amsterdam, The Netherlands [C. R. F., P. P., C. N. P.]

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 10³, 18 x 10⁴, 18 x 10⁵, and 18 x 10⁶ 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.

¹ This work was supported partially by grants from the Istituto Superiore di Sanita' (Italy-USA Program on Therapy of Neoplasias) and the Italian Association for Cancer Research.

² To whom requests for reprints should be addressed.

Received 8/23/90. Accepted 2/19/91.