Pilot study of interleukin-2 and lymphokine-activated killer cells combined with immunomodulatory doses of chemotherapy and sequenced with interferon alfa-2a in patients with metastatic melanoma and renal cell carcinoma
Sznol, M.; Clark, J.W.; Smith, J.W.; Steis, R.G.; Urba, W.J.; Rubinstein, L.V.; VanderMolen, L.A.; Janik, J.; Sharfman, W.H.; Fenton, R.G.
Journal of the National Cancer Institute 84(12): 929-937
1992
ISSN/ISBN: 0027-8874 PMID: 1629914 Document Number: 404075
Background: Experiments in animal tumor models suggest that the antitumor effects of interleukin-2 (IL-2) or IL-2 in combination with lymphokine-activated killer (LAK) cells can be enhanced by chemotherapy agents such as cyclophosphamide or doxorubicin or by the biologic agent interferon-.alpha. Purpose: We determined the toxicity and clinical response rate of an IL-2-LAK cell regimen modified by the addition of moderate, immunomodulatory doses of chemotherapy and sequenced with interferon-alpha-2a (IFN .alpha.-2a) in patients with metastatic melanoma and renal cell carcinoma. Methods: IL-2 (3-6 million units/m2 per day) was administered by continuous infusion on days 0-5 and days 11-16. LAK cells were infused on days 11 and 12 or on days 11, 12, and 14. Low doses of cyclophosphamide (300 mg/m2) and doxorubicin (25 mg/m2) were given on day 9 before the LAK cell infusions. Following the IL-2LAK cell infusion, IFN .alpha.-2a (12 million units/m2) was adminsitered for a total of nine doses to complete a cycle of treatment. A total of 89 patients were enrolled in the study. Results: For each histology, there were eight partial responses in 40 assessable patients, for an overall response rate of 20% (90% confidence interval = 10%-33%). The median response duration was 5 months, although two patients with renal cell carcinoma and one patient with metastatic melanoma had almost complete disappearance of tumor and are still responding after 26+, 22+, and 26+ months, respectively. Toxic effects were severe in patients receiving the highest dose of IL-2 adminsitered in this study and similar to those reported with other high-dose IL-2-LAK cell regimens. Although toxic effects were completely reversible in most patients, there were four treatment-related deaths. Conclusions: This regimen is active in patients with metastatic melanoma and renal cell carcinoma and produces meaningful responses in a small percentage of these patients; however, it is not clear whether cyclophosphamide, doxorubicin, and IFN .alpha.-2a as used in this protocol appreciably augmented the antitumor activity of the IL-2-LAK cell regimen.