Rituximab (Rituxan) is a genetically engineered chimeric murine/human monoclonal antibody that binds specifically to CD20 on pre-B and mature B lymphocytes. While binding of the Fab domain may induce apoptosis, the Fc domain recruits immune effector functions to mediate lysis of the B cell. Interleukin-12 (IL-12) has been shown to facilitate cytolytic T-cell responses, promote the development of Th1-type helper T cells, enhance the lytic activity of natural killer (NK) cells, and induce the secretion of interferon gamma(Drug information on interferon gamma) by both T and NK cells. Therefore, we hypothesized that combining IL-12 with rituximab(Drug information on rituximab) would augment the immune mediated cell lysis induced by rituximab.
We conducted a phase I study of IL-12 in combination with rituximab in adult patients with B-cell non-Hodgkin’s lymphoma to determine the optimal immunologic dose of this combination. Rituximab was administered at a fixed dose of 375 mg/m2 by intravenous infusion weekly for 4 weeks, while IL-12 was given subcutaneously twice weekly for up to 6 months. The starting dose of IL-12 was 30 ng/kg; this was escalated with each cohort of six patients to a maximum of 500 ng/kg.
Forty-three patients (4 small lymphocytic, 20 follicular, 10 diffuse large cell, 6 mantle cell, 2 lymphoplasmacytic, 1 T-cell-rich B cell) were treated. Constitutional symptoms and liver enzyme elevations were found to be dose-limiting. A greater than 100% increase from baseline in the serum levels of interferon gamma and inducible protein 10 (IP-10) in response to IL-12 were seen at IL-12 doses of 100, 300, and 500 ng/kg. Significant constitutional symptoms and liver enzyme elevations were seen at the 300-ng/kg dose level, necessitating a dose reduction in 4 of 9 patients.
Dose-limiting toxicity was seen at 500 ng/kg. As the goal of the study was to determine the optimal immunologic dose of IL-12 when given in combination with rituximab rather than the maximum tolerated dose, the recommended immunologic dose of IL-12 is therefore 100 ng/kg subcutaneously twice weekly.
Objective responses were seen in 29 of 43 patients (69%; 3/4 small lymphocytic, 13/20 follicular, 6/10 large cell, 5/6 mantle cell, 1/2 lymphoplasmacytic, 1/1 T-cell-rich B cell).
CONCLUSION: These data suggest that this is an active combination. Further studies of this combination in B-cell non-Hodgkin’s lymphoma are planned.