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Aditi H. Mandpe, MD; Kangla Tsung, PhD; Jeffrey A. Norton, MD

Arch Otolaryngol Head Neck Surg. 2003;129:786-792.

Objective  To develop a murine model of effective treatment with immunotherapy for established head and neck squamous cell carcinoma.

Design  Prospective animal study.

Subjects  Female C3H mice, 8 to 12 weeks old.

Interventions  A subcutaneous inoculation of 2 x 10⁵ SCC VII cells in C3H mice was established for 7 to 12 days. Tests for concomitant immunity were performed, with and without interleukin 12 modification. Tumors were also tested for responsiveness to interleukin 12 (5 mice) and to cyclophosphamide followed by interleukin 12 (5 mice). SCC VII tumors in 24 mice were treated with interleukin 12 followed by cyclophosphamide and interleukin 12. Five mice with tumors treated with isotonic sodium chloride solution served as controls. Tumors were measured 3 to 4 times weekly, and cure was defined as complete regression of the tumor for at least 60 days. Cured mice were rechallenged with 2 x 10⁵ SCC VII cells to verify antitumor immunity. Immunohistochemistry of regressing tumors was performed for CD4⁺ and CD8⁺ T cells.

Results  Tumor-bearing mice easily developed second tumors when challenged with 2 x 10⁵ tumor cells in the opposite flank. However, interleukin 12 treatment provided immunity to second tumors in 8 (100%) of 8 mice when started at day 4 and in 2 (40%) of 5 when treated from day 7. SCC VII did not respond to standard interleukin 12 or cyclophosphamide plus interleukin 12 therapy. Seventy-five percent of animals (18/24) treated with interleukin 12 followed by cyclophosphamide plus interleukin 12 were successfully cured, and all cured mice resisted subsequent challenge with SCC VII. Immunohistochemistry of regressed tumors showed an intense CD4⁺ and CD8⁺ infiltrate that was absent in the untreated and nonresponding tumors.

Conclusions  Nonimmunogenic SCC VII is a nonimmunogenic tumor that can be converted into an immunogenic tumor with interleukin 12 treatment. Additional treatment with cyclophosphamide plus interleukin 12 leads to complete regression in 75% of mice.

From the Departments of Otolaryngology–Head and Neck Surgery (Dr Mandpe) and Surgery (Drs Tsung and Norton), University of California, San Francisco, and the Surgical Service Veterans Affairs Medical Center, San Francisco (Drs Mandpe, Tsung, and Norton). The authors have no relevant financial interest in this article.

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