title: Phase I trial of sequential cyclophosphamide, cyclosporin A, and interferon-alpha in patients with cancer: attempt to induce autologous graft-versus-host reaction to elicit an antitumor response.
abstract: Previous reports of autologous bone marrow transplant (auto-BMT) have demonstrated that myeloablative therapy followed by cyclosporin A (CsA), with and without interferon (IFN), can generate autoreactive cytotoxic T lymphocytes (auto-CTL) with potential therapeutic benefit. This is the first report of an attempt to generate auto-CTL using CsA and IFN after a non-myeloablative regimen. Cyclophosphamide (CTX) 1,200 mg/m2 i.v. day 1 was followed by CsA and IFN-alpha days 2-28, administered in a sequential three-step Phase I dose-escalation scheme. Patients were evaluated twice weekly for clinical evidence of graft-versus-host (GVH) reaction. Peripheral blood mononuclear cells (PBMCs) were obtained before treatment, at time of clinical GVH reaction, and days 21 and 28, and analyzed for auto-CTL, natural killer (NK) cell, and lymphokine-activated killer (LAK) cell activity. Patients also underwent punch skin biopsy at the time of clinical GVH reaction or day 21 to identify histologic evidence of GVH. Fourteen patients completed therapy and were evaluable for immunologic studies and anti-tumor response. No increase in auto-CTL, NK cell, or LAK cell activity was seen. Clinical or histologic evidence of GVH reaction did not occur. We conclude that this myelosuppressive dose of CTX combined with CsA and IFN is unable to generate clinical or immunologic evidence of an auto-GVH reaction. Further efforts are warranted to evaluate other therapeutic attempts to generate auto-CTL with anti-tumor activity based on preliminary results of clinical benefit in auto-BMT.
authors.affiliation: Division of Hematology-Oncology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: B G
authors.initials: BG
authors.lastname: Redman
authors.forename: T H
authors.initials: TH
authors.lastname: Chou
authors.forename: M
authors.initials: M
authors.lastname: Zalupski
authors.forename: J
authors.initials: J
authors.lastname: Uberti
authors.forename: L
authors.initials: L
authors.lastname: Flaherty
authors.forename: M
authors.initials: M
authors.lastname: Dan
authors.forename: L
authors.initials: L
authors.lastname: Sensenbrenner
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects*; D003520:Cyclophosphamide / Q000627:therapeutic use; D016572:Cyclosporine / Q000627:therapeutic use; D003601:Cytotoxicity Tests, Immunologic; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006087:Graft vs Host Reaction / Q000187:drug effects*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D014182:Transplantation, Autologous
chemical_list: D016898:Interferon-alpha; D016572:Cyclosporine; D003520:Cyclophosphamide