title: Phase 1 study of interleukin-12 in combination with rituximab in patients with B-cell non-Hodgkin lymphoma.
abstract: Rituximab is a chimeric murine/human monoclonal antibody that binds to CD20 on B lymphocytes. Although binding of the Fab domain may induce apoptosis, the Fc domain recruits immune effector functions to mediate cell lysis. Interleukin-12 (IL-12) facilitates cytolytic T-cell responses, enhances the lytic activity of natural killer (NK) cells, and induces the secretion of interferon gamma (IFN-gamma) by both T and NK cells. Therefore, the hypothesis was considered that combining IL-12 with rituximab would augment the immune-mediated cell lysis induced by rituximab. A phase 1 study of IL-12 in combination with rituximab was conducted in 43 adults with B-cell lymphoma to determine the optimal immunologic dose of this combination. Rituximab was administered at a dose of 375 mg/m(2) by intravenous infusion weekly for 4 weeks, and IL-12 was given subcutaneously twice weekly. The starting dose of IL-12 was 30 ng/kg and this was escalated to 500 ng/kg. Constitutional symptoms and liver enzyme elevations at 500 ng/kg of IL-12 were dose limiting. A greater than 20-fold increase in the serum levels of IFN-gamma and a 2.5- to 5-fold increase in inducible protein 10 (IP-10) levels was seen at IL-12 doses of 100 ng/kg or greater. Objective responses occurred in 29 of the 43 patients (69%), with 8 of 11 complete responses seen at IL-12 doses of 300 ng/kg or greater. The optimal immunologic dose of IL-12 in combination with rituximab was determined to be 300 ng/kg subcutaneously twice weekly starting on day 2. These data suggest that IL-12 and rituximab is an active combination and further studies of this combination in B-cell non-Hodgkin lymphoma are warranted.
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA. ansell.stephen@mayo.edu
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kurtin
authors.forename: Jeff A
authors.initials: JA
authors.lastname: Sloan
authors.forename: Diane F
authors.initials: DF
authors.lastname: Jelinek
authors.forename: Kyle G
authors.initials: KG
authors.lastname: Howell
authors.forename: Svetomir N
authors.initials: SN
authors.lastname: Markovic
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Habermann
authors.forename: George G
authors.initials: GG
authors.lastname: Klee
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Atherton
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000473:pathology; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016131:Lymphocyte Subsets; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D000069283:Rituximab; D013601:T-Lymphocytes / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D018664:Interleukin-12; D000069283:Rituximab; D007371:Interferon-gamma