Phase I Study of Interleukin-12 in Combination With Rituximab in Patients With B-Cell Non-Hodgkin’s Lymphoma

March 1, 2001

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

Rituximab (Rituxan) is a genetically engineered chimericmurine/human monoclonal antibody that binds specifically to CD20 on pre-B andmature B lymphocytes. While binding of the Fab domain may induce apoptosis, theFc 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 activityof natural killer (NK) cells, and induce the secretion of interferon gamma byboth T and NK cells. Therefore, we hypothesized that combining IL-12 withrituximab would augment the immune mediated cell lysis induced by rituximab.

We conducted a phase I study of IL-12 in combination withrituximab in adult patients with B-cell non-Hodgkin’s lymphoma to determinethe optimal immunologic dose of this combination. Rituximab was administered ata fixed dose of 375 mg/m2 by intravenous infusion weekly for 4 weeks, whileIL-12 was given subcutaneously twice weekly for up to 6 months. The startingdose of IL-12 was 30 ng/kg; this was escalated with each cohort of six patientsto a maximum of 500 ng/kg.

Forty-three patients (4 small lymphocytic, 20 follicular, 10diffuse large cell, 6 mantle cell, 2 lymphoplasmacytic, 1 T-cell-rich B cell)were treated. Constitutional symptoms and liver enzyme elevations were found tobe dose-limiting. A greater than 100% increase from baseline in the serum levelsof interferon gamma and inducible protein 10 (IP-10) in response to IL-12 wereseen at IL-12 doses of 100, 300, and 500 ng/kg. Significant constitutionalsymptoms 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 thestudy was to determine the optimal immunologic dose of IL-12 when given incombination with rituximab rather than the maximum tolerated dose, therecommended immunologic dose of IL-12 is therefore 100 ng/kg subcutaneouslytwice weekly.

Objective responses were seen in 29 of 43 patients (69%; 3/4small lymphocytic,  13/20 follicular, 6/10 large cell, 5/6 mantle cell, 1/2 lymphoplasmacytic, 1/1T-cell-rich B cell).

CONCLUSION: These data suggest that this is an activecombination. Further studies of this combination in B-cell non-Hodgkin’slymphoma are planned.

Click here to read Dr. Bruce Cheson's commentary on this abstract.