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Evidence for Local and Systemic Activation of Immune Cells by Peritumoral Injections of Interleukin 2 in Patients with Advanced Squamous Cell Carcinoma of the Head and Neck¹

Departments of Pathology [T. L. W., E. L., D. V., L. B., R. B. H.], Otolaryngology [H. H., C. S., J. T. J., E. M.], and Medicine [R. B. H., J. M. K., D. R. V.], University of Pittsburgh School of Medicine, Pittsburgh Cancer Institute, [T. L. W., E. L., H. H., D. V., J. B., C. S., J. T. J., E. M., R. B. H., J. M. K., D. R. V.], and Eye and Ear Institute [H. H., C. S., J. T. J., E. M.], Pittsburgh, Pennsylvania 15213; and Department of Otolaryngology, Albert Einstein School of Medicine, New York, New York 10708 [J. R.]

² To whom requests for reprints should be addressed, at Pittsburgh Cancer Institute, W1041 Biomedical Science Tower, DeSoto at O'Hara Street, 10th Floor West Wing, Pittsburgh, PA 15213.

Interleukin 2 (IL2) was injected peritumorally and intranodally in 36 patients with unresectable squamous cell carcinoma of the head and neck enrolled in an Eastern Cooperative Oncology Group-sponsored phase lb trial (EST P-Z388). Groups of 6 patients received escalating doses(200, 2 x 10³, 2 x 10⁴, 2 x 10⁵, 2 x 10⁶, and 4 x 10⁶ units) of IL2 daily 5 times/week for 2 weeks. Tumor biopsies were obtained before and after IL2 therapy. Tumor tissue was provided for histology, and the remaining fresh tissue was divided for snap-freezing in –75°C and for separation of tumor-infiltrating lymphocytes (TIL) and tumor cells. Immunophenotyping of TIL performed on cryostat sections of paired pre- and post-IL2 biopsy tissues showed increases after IL2 therapy in the number of T-cells (P = 0.005), natural killer (NK; CD16⁺) cells (P = 0.0001), CD25⁺ cells (P = 0.004), and HLA-DR⁺ cells (P = 0.001) accumulating in the tumor stroma. In the tumor parenchyma, NK cells (P = 0.0001) and HLA-DR⁺ cells (P = 0.003) were increased after IL2 therapy. The T:NK cell ratios in the tumor stroma and parenchyma were decreased after therapy, suggesting selective accumulation of NK cells. By flow cytometry, TIL recovered from post-IL2 biopsy tissues were enriched (P < 0.05) in CD3^–CD56⁺ (NK) cells. In situ hybridization with [³⁵S] cDNA probes for cytokines and IL2 receptors indicated that the numbers of cells expressing mRNA for IL2, tumor necrosis factor , IL1-β, -interferon, transforming growth factor β, and IL2 receptor p55 or p70 were increased in post-IL2 biopsy tissues as compared to pre-IL2 tissues. Cytolytic activity of TIL isolated from post-IL2 tissues was also increased, as determined in 4-h ⁵¹Cr release assays against K562 targets (12 ± 3 mean lytic units/10⁷ cells ± SEM pre-IL2 versus 46 ± 13 post-IL2; n = 16) and against autologous tumor (13 ± 8 versus 68 ± 26; n = 9). Fresh TIL of one clinical responder showed relatively high levels (195 lytic units) of autotumor cytotoxicity after IL2 therapy versus no activity prior to therapy. In the blood, NK and lymphokine-activated killer cell activity, and percentages of CD3^–CD56⁺ NK cells and of activated (CD25⁺) T-lymphocytes were increased for all doses of IL2. A significant dose-response effect was observed for the percentage of CD3^–CD56⁺ NK cells and lymphokine activated killer cell cytotoxicity against autologous tumor, with the highest values observed at the two highest doses of IL2. Our data indicate that local as well as systemic activation of antitumor effector cells occurred during local administration of IL2 in patients with squamous cell carcinoma of the head and neck.

¹ The clinical trial described was sponsored by the Eastern Cooperative Oncology Group. This study was supported in part by the Pathology Education and Research Foundation, University of Pittsburgh, and by the Mary Hillman Jennings Foundation Grant to the Eye and Ear Institute.

³ Present address: Hematology/Oncology Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 4/19/93. Accepted 9/22/93.

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