Combination immunotherapy of B-cell non-Hodgkin's lymphoma with rituximab and interleukin-2: a preclinical and phase I study.

Abstract

PURPOSE:

Cytokine-induced modulation of innate immunity is being explored to enhance the activity of monoclonal antibodies. Severe combined immunodeficient (SCID) mice engrafted with peripheral blood leukocytes (PBLs) from Epstein Barr virus-seropositive donors develop human B-cell non-Hodgkin's lymphomas [B-NHLs (hu-PBL-SCID mouse model)]. We used this hu-PBL-SCID mouse model to study the synergism between interleukin (IL)-2 and rituximab. We also conducted a phase I trial of IL-2 and rituximab in relapsed B-NHL to study whether expansion of natural killer (NK) cells and enhanced cellular cytotoxicity could be safely accomplished in vivo.

EXPERIMENTAL DESIGN:

Hu-PBL-SCID mice were treated with various schedules of rituximab and IL-2, with survival as the end point. Patients with relapsed B-NHL received rituximab (375 mg/m2 weekly x 4) followed by daily low-dose IL-2 (1 MIU/m2/day x 4 weeks) with pulses of intermediate-dose IL-2 (3-15 MIU/m2). Toxicity, NK cell numbers, and cellular cytotoxicity were measured.

RESULTS:

In the hu-PBL-SCID mouse, the combination of rituximab and IL-2 showed greater activity against B-NHL than either agent alone. Treatment was most effective when IL-2 was given before rituximab. Twelve patients with heavily pretreated B-NHL entered the phase I trial. Toxicity was manageable, and responses were observed. NK cell expansion and enhanced cellular cytotoxicity against a B-cell lymphoma target were observed but did not correlate with response.

CONCLUSIONS:

The combination of IL-2 and rituximab is synergistic against B-NHL in the hu-PBL-SCID model. In the phase I trial, a sequential combination of rituximab and IL-2 was well tolerated and achieved biological end points. Responses were observed.

• Authors: Charles F Eisenbeis, Andrew Grainger, Beth Fischer, Robert A Baiocchi, Lester Carrodeguas, Sameek Roychowdhury, Lei Chen, Amy L Banks, Thomas Davis, Donn Young, Nicole Kelbick, Julie Stephens, John C Byrd, Michael R Grever, Michael A Caligiuri, Pierluigi Porcu
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 18 Pt 1 Pg. 6101-10 (Sep 15 2004) ISSN: 1078-0432 [Print] United States
• PMID: 15447996 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Murine-Derived
• Antineoplastic Agents
• Interleukin-2
• Rituximab

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Antibodies, Monoclonal (administration & dosage)
• Antibodies, Monoclonal, Murine-Derived
• Antineoplastic Agents (administration & dosage)
• Combined Modality Therapy (methods)
• Female
• Humans
• Immunotherapy (methods)
• Interleukin-2 (administration & dosage, metabolism)
• Killer Cells, Natural (immunology)
• Leukocytes (immunology)
• Leukocytes, Mononuclear (metabolism)
• Lymphoma, B-Cell (immunology, therapy)
• Lymphoma, Non-Hodgkin (immunology, therapy)
• Male
• Mice
• Mice, SCID
• Middle Aged
• Rituximab
• Time Factors
• Treatment Outcome