title: Interferon-alpha primed tumor-infiltrating lymphocytes combined with interleukin-2 and interferon-alpha as therapy for metastatic renal cell carcinoma.
abstract: Murine models demonstrate therapeutic synergy for the combination of interleukin-2, interferon-alpha 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-alpha and interleukin-2. Patients received interferon-alpha before radical nephrectomy; in vivo primed tumor-infiltrating lymphocytes were isolated and expanded in vitro. Low dose continuous infusion interleukin-2 at a dose of 2 x 10(6) units per m.2 per day was administered for 96 hours during each treatment week and interferon-alpha was administered as a subcutaneous injection at a dose of 6 x 10(6) 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-alpha 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 response (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-alpha primed tumor-infiltrating lymphocytes, low dose continuous infusion interleukin-2 and interferon-alpha can induce significant and durable antitumor responses in some patients with advanced renal cell carcinoma.
authors.affiliation: Department of Surgery, UCLA School of Medicine.
authors.forename: A
authors.initials: A
authors.lastname: Belldegrun
authors.forename: W
authors.initials: W
authors.lastname: Pierce
authors.forename: R
authors.initials: R
authors.lastname: Kaboo
authors.forename: C L
authors.initials: CL
authors.lastname: Tso
authors.forename: H
authors.initials: H
authors.lastname: Shau
authors.forename: P
authors.initials: P
authors.lastname: Turcillo
authors.forename: N
authors.initials: N
authors.lastname: Moldawer
authors.forename: S
authors.initials: S
authors.lastname: Golub
authors.forename: J
authors.initials: J
authors.lastname: deKernion
authors.forename: R
authors.initials: R
authors.lastname: Figlin
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000096:biosynthesis; D002292:Carcinoma, Renal Cell / Q000556:secondary* / Q000628:therapy*; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects; D016898:Interferon-alpha / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000473:pathology / Q000628:therapy*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy; D010641:Phenotype; D011300:Preoperative Care; D016896:Treatment Outcome
chemical_list: D015703:Antigens, CD; D016898:Interferon-alpha; D007376:Interleukin-2