title: A pilot study of denileukin diftitox (DD) in combination with high-dose interleukin-2 (IL-2) for patients with metastatic renal cell carcinoma (RCC).
abstract: High-dose (HD) IL-2 is approved to treat renal cell carcinoma (RCC) with modest response rates and significant toxicity. Enhancement of cytotoxic T-cell activity by IL-2 is 1 mechanism of action. IL-2 also stimulates regulatory T lymphocytes (Tregs), which are associated with poor prognosis. Favorable outcomes are associated with greater rebound absolute lymphocyte count (Fumagalli 2003). DD depletes IL-2 receptor (CD25 component) expressing cells. We hypothesized that sequential therapy could complement each other; DD would deplete Tregs so IL-2 could more effectively stimulate proliferation and activity of cytotoxic T lymphocytes. Patients (n=18) received standard HD IL-2 and 1 dose of DD daily for 3 days; periodic flow cytometry and complete blood counts were performed. Group A included 3 patients to assess safety only with DD 6 μg/kg between the IL-2 courses. Group B included 9 patients at 9 μg/kg DD before the IL-2 courses. Group C included 6 patients at 9 μg/kg DD between the IL-2 courses. Efficacy using the RECIST criteria was assessed after the treatment. Fifteen patients from a study of IL-2 without DD served as controls for toxicity comparison and 13 of these for flow cytometry comparisons. No unusual toxicity was noted. For group B/C patients receiving DD, the median decline in Tregs was 56.3% from pre-DD to post-DD (P=0.013). Peak absolute lymphocyte count change from baseline was +9980/μL for group B, +4470/μL for group C, and +4720/μL for the controls (P=0.005 B vs. C). The overall response rate was 5 of 15 (33%); 3 of 9 (33%) and 2 of 6 (33%) for groups B and C, respectively, including 2 patients with sarcomatoid RCC and 1 with earlier sunitinib therapy.
authors.affiliation: Department of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Atchison
authors.forename: John
authors.initials: J
authors.lastname: Eklund
authors.forename: Brenda
authors.initials: B
authors.lastname: Martone
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Adi
authors.initials: A
authors.lastname: Gidron
authors.forename: Gary
authors.initials: G
authors.lastname: Macvicar
authors.forename: Alfred
authors.initials: A
authors.lastname: Rademaker
authors.forename: Charles
authors.initials: C
authors.lastname: Goolsby
authors.forename: Laura
authors.initials: L
authors.lastname: Marszalek
authors.forename: James
authors.initials: J
authors.lastname: Kozlowski
authors.forename: Norm
authors.initials: N
authors.lastname: Smith
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Kuzel
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy*; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D004167:Diphtheria Toxin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy*; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D004167:Diphtheria Toxin; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox