Phase 1 study of interleukin-12 in combination with rituximab inpatients with B-cell non-Hodgkin's lymphoma

Stephen Maxted Ansell, Thomas Elmer Witzig, Paul J. Kurtin, Jeff A Sloan, Diane F Jelinek, Kyle G. Howell, Svetomir Nenad Markovic, Thomas Matthew Habermann, George G. Klee, Pamela J. Atherton, Charles Erlichman

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120 Citations (Scopus)

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 γ (IFN-γ) 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/m2 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 500ng/kg of IL-12 were dose limiting. A greater than 20-fold increase in the serum levels of IFN-γ 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's lymphoma are warranted.

Original languageEnglish (US)
Pages (from-to)67-74
Number of pages8
JournalBlood
Volume99
Issue number1
DOIs
StatePublished - Jan 1 2002

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B-Cell Lymphoma
Interleukin-12
Non-Hodgkin's Lymphoma
Inpatients
Cells
Interferons
Rituximab
Natural Killer T-Cells
T-cells
Lymphocytes
Intravenous Infusions
Natural Killer Cells
Liver
B-Lymphocytes
Monoclonal Antibodies
Apoptosis
T-Lymphocytes

ASJC Scopus subject areas

  • Hematology

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Phase 1 study of interleukin-12 in combination with rituximab inpatients with B-cell non-Hodgkin's lymphoma. / Ansell, Stephen Maxted; Witzig, Thomas Elmer; Kurtin, Paul J.; Sloan, Jeff A; Jelinek, Diane F; Howell, Kyle G.; Markovic, Svetomir Nenad; Habermann, Thomas Matthew; Klee, George G.; Atherton, Pamela J.; Erlichman, Charles.

In: Blood, Vol. 99, No. 1, 01.01.2002, p. 67-74.

Research output: Contribution to journalArticle

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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 γ (IFN-γ) 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/m2 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 500ng/kg of IL-12 were dose limiting. A greater than 20-fold increase in the serum levels of IFN-γ 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's lymphoma are warranted.",
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AU - Howell, Kyle G.

AU - Markovic, Svetomir Nenad

AU - Habermann, Thomas Matthew

AU - Klee, George G.

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