Therapeutic activity of L19-IL2, unconjugated rIL-2 and rituximab in mono- and combination therapy against localized Ramos lymphoma xenografts. (A) SCID mice bearing established sc Ramos lymphoma xenografts (50-100 mm3) were injected IV with 20 μg of the fusion protein L19-IL2 (■), the corresponding dose (6.6 μg) of nontargeted rIL-2 (▴), 200 μg rituximab (●), or control saline (×) on days 8, 11, 14, and 17 (Q3D × 4). While the nontargeted administration of free rIL-2 did not exhibit significant therapeutic activity, L19-IL2 significantly reduced tumor growth rate (L19-IL2 vs saline: P = .024; L19-IL2 vs rIL-2: P = .044). (B) For combination therapy studies, lymphoma-bearing mice were injected IV with either 200 μg rituximab + low-dose unconjugated rIL-2 (2.2 μg; ▵), 200 μg rituximab + high-dose unconjugated rIL-2 (6.6 μg; ▴), 200 μg rituximab + low-dose L19-IL2 (6.6 μg, corresponding to 2.2 μg rIL-2; □), 200 μg rituximab + high-dose L19-IL2 (20 μg, corresponding to 6.6 μg rIL-2; ■), or saline (×) on days 8, 11, 14, and 17 (Q3D × 4). Combination therapy of L19-IL2 and rituximab exhibited a strong therapeutic benefit as compared with the combination of rIL-2 and rituximab (L19-IL2 vs rIL-2: P < .001 for all dose levels) and induced CRs in 4 of 5 cases at both dose levels. While mice with CR treated with low-dose L19-IL2 and rituximab relapsed after a remission duration of 21, 48, 50, and 81 days, respectively, all CRs in the higher dose L19-IL2 group were durable for a period of 1 year at the time of the writing of this article. Data represent mean tumor volumes (± SE). Arrows, days of treatment.
