Interferon-α Primed Tumor-Infiltrating Lymphocytes Combined with Interleukin-2 and Interferon-α as Therapy for Metastatic Renal Cell Carcinoma

Abstract

Murine models demonstrate therapeutic synergy for the combination of interleukin-2, interferon-α and tumor-infiltrating lymphocytes. We treated 11 patients with metastatic renal cell carcinoma with a novel regimen consisting of in vivo primed tumor-infiltrating lymphocytes, interferon-α and interleukin-2. Patients received interferon-α before radical nephrectomy; in vivo primed tumor-infiltrating lymphocytes were isolated and expanded in vitro. Low dose continuous infusion inter-leukin-2 at a dose of 2 × 106 units per m2 per day was administered for 96 hours during each treatment week and interferon-α was administered as a subcutaneous injection at a dose of 6 × 106 units per m.2 per day on days 1 and 4 of the interleukin-2 infusion. No therapy was given during the last 3 days of a treatment week. One course of therapy consisted of 3 weeks of therapy followed by 3 weeks of rest. Patients were treated until maximal response, disease progression or dose limiting toxicity. A maximum of 6 courses of therapy were administered. Eleven patients underwent interferon-α priming and subsequent radical nephrectomy. In vivo primed tumor-infiltrating lymphocytes were successfully expanded in all 11 patients with an expansion index of greater than 170. In vivo primed tumor-infiltrating lymphocytes maintained their lytic activity for greater than 5 to 8 weeks in culture as demonstrated in the 4-hour 51chromium release assay. Ten patients underwent multimodality biological therapy and 3 (30%, 95% confidence interval 6 to 65%) have achieved complete responses (2 clinical and 1 surgical) with durations of 24+, 23+ and 5+ months. Patients with stable disease received no additional therapy. No deaths and no grade 4 toxicities occurred. Immunotherapy using a combination of interferon-α primed tumor-infiltrating lymphocytes, low dose continuous infusion interleukin-2 and interferon-α: can induce significant and durable antitumor responses in some patients with advanced renal cell carcinoma.