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Blood, 1 January 2002, Vol. 99, No. 1, pp. 67-74
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Phase 1 study of interleukin-12 in combination with rituximab in
patients with B-cell non-Hodgkin lymphoma
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, and
Charles Erlichman
From the Division of Hematology, Division of
Hematopathology, Department of Immunology, Department of Laboratory
Medicine, Department of Biostatistics, and Division of Medical
Oncology, Mayo Clinic, Rochester, MN.
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  (IFN-) 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 500 ng/kg
of IL-12 were dose limiting. A greater than 20-fold increase in the
serum levels of IFN- 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.
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