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Clinical and Immunomodulatory Effects of Combination Immunotherapy with Low-Dose Interleukin 2 and Tumor Necrosis Factor in Patients with Advanced Non-Small Cell Lung Cancer: A Phase I Trial¹

Departments of Thoracic Surgery [S. C. Y., K. D. F., A. M-R., J. A. R.], Tumor Biology [E. A. G., J. C., L. B. O-S., J. A. R.], and Clinical Immunology and Biological Therapy [D. R. P.], Division of General Surgery [E. A. G.], and Head and Neck/Thoracic Medical Oncology Section [J. L., W. K. H.], The University of Texas M. D. Anderson Cancer Center; and the Department of General Surgery [S. C. Y.], the University of Texas Health Science Center at Houston, Houston, Texas 77030

Sixteen patients with metastatic non-small cell lung cancer were treated with a combination of simultaneous low-dose interleukin 2 (IL-2) and tumor necrosis factor . The purpose of this phase I dose escalation trial was to assess the clinical toxicities, immunomodulatory effects, and antitumor efficacy of this combination. Patients received a continuous daily i.v. infusion of 6 x 10⁶ IU/m² of IL-2 for 5 days and a concomitant daily i.m. dose of tumor necrosis factor on each day of IL-2 administration. Tumor necrosis factor administration started at a dose of 25 µg/m²/day (level I) for seven patients, 50 µg/m²/day (level II) for seven patients, and 100 µg/m²/day (level III) for two patients. Treatment was given at 3-week intervals. Only one patient required monitoring by an intensive care unit during therapy. Major toxic effects included fever, local skin reaction at the i.m. injection site, pancytopenia, and general malaise, all of which were reversible within 48 h of cessation of therapy. Dose level II was determined to be the maximum tolerated dose, with the dose-limiting toxicity being thrombocytopenia (<50,000/µl). In 12 evaluable patients, one partial and three minor tumor regressions were observed. Seven patients with progressive disease before entry into this study had radiographic stabilization of their disease (median, 12 weeks) before termination of therapy due to progression. All patients exhibited biological responses including augmented lymphokine-activated killer and natural killer cell activities while receiving therapy, as assessed by the cytolysis of Raji and K562 targets in vitro. Enhanced lysis of autologous tumor during therapy was demonstrated for four patients with available tumor samples. Serum levels of IL-2 were detected by enzymelinked immunosorbent assay 2 weeks after cessation of therapy. This serum IL-2 had biological activity, which was evident from the ability to induce proliferation of NK-8 cells (an IL-2-dependent cell line) which was abrogated by anti-IL-2 antibody.

¹ This work was supported by NIH Grants CA45225 (E. A. G.) and CA09611 (J. A. R.).

² To whom requests for reprints should be addressed, at the Department of Thoracic Surgery, Box 109, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.

Received 10/ 2/90. Accepted 5/ 3/91.

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