Combination immunotherapy of B-cell non-Hodgkin's lymphoma with rituximab and interleukin-2: a preclinical and phase I study
| Autor: | 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 |
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| Rok vydání: | 2004 |
| Předmět: |
Adult
Aged 80 and over Male Lymphoma B-Cell Time Factors Lymphoma Non-Hodgkin Antibodies Monoclonal Antineoplastic Agents Mice SCID Middle Aged Combined Modality Therapy Killer Cells Natural Antibodies Monoclonal Murine-Derived Mice Treatment Outcome Leukocytes Leukocytes Mononuclear Animals Humans Interleukin-2 Female Immunotherapy Rituximab Aged |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 10(18 Pt 1) |
| ISSN: | 1078-0432 |
| Popis: | 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.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.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.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. |
| Databáze: | OpenAIRE |
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