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: Stephen M Ansell, Thomas E Witzig, Paul J Kurtin, Jeff A Sloan, Diane F Jelinek, Kyle G Howell, Svetomir N Markovic, Thomas M Habermann, George G Klee, Pamela J Atherton, Charles Erlichman
• Journal: Blood (Blood) Vol. 99 Issue 1 Pg. 67-74 (Jan 01 2002) ISSN: 0006-4971 [Print] United States
• PMID: 11756154 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adjuvants, Immunologic
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Murine-Derived
• Antigens, CD20
• Antineoplastic Agents
• Interleukin-12
• Rituximab
• Interferon-gamma

Topics

• Adjuvants, Immunologic (therapeutic use)
• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (administration & dosage, adverse effects, therapeutic use)
• Antibodies, Monoclonal, Murine-Derived
• Antigens, CD20 (immunology)
• Antineoplastic Agents (administration & dosage, adverse effects, therapeutic use)
• B-Lymphocytes (pathology)
• Female
• Humans
• Immunotherapy
• Interferon-gamma (blood)
• Interleukin-12 (administration & dosage, adverse effects, therapeutic use)
• Lymphocyte Subsets
• Lymphoma, B-Cell (immunology, pathology, therapy)
• Male
• Middle Aged
• Rituximab
• T-Lymphocytes (pathology)
• Treatment Outcome