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

Purpose: Cytokine-induced modulation of innate immunity is being explored to enhance the activity of monoclonal antibodies. Severe combined immmmodeficient (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 rituximah 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 rituximalb and IL-2, with survival as the end point. Patients with relapsed B-NHL received rituximab (375 mg/m(2) weekly X 4) followed by daily lowdose IL-2 (I MIU/m(2)/day X 4 weeks) with pulses of intermediate-dose IL-2 (3-15 MIU/m(2)). 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 rituximah and IL-2 was well tolerated and achieved biological end points. Responses were observed.