Efficacy of anti-CTLA-4 antibody in the SA1N tumor model when combined with dexamethasone

2202 CTLA-4 is a negative costimulatory molecule expressed by multiple T cell subsets. Inhibition CTLA-4 activity by monoclonal antibodies has been shown to enhance anti-tumor responses in a variety of murine models. Ipilimumab (MDX-010; BMS-734016), a human antibody against CTLA-4, has shown activity against multiple f tumor types in clinical trials. Anti-cancer responses have been frequently associated with inflammatory adverse events that are suggestive of T cell activation, such as colitis, rash, and hypopituitarism. Serious adverse events are managed by cessation of antibody and the use immunosuppressive doses of corticosteroids, while durable anti-tumor responses have been maintained. Using a murine Sa1N fibrosarcoma model sensitive to anti-CTLA-4 monotherapy, the effect of dexamethasone (Dex) on anti-tumor activity was investigated. Sa1N cells were implanted in A/J mice and treated at ~100 mm3 with an anti-CTLA-4 antibody (9D9, 10 mg/kg), Q3Dx4. Dex (1 or 10 mg/kg; Q2Dx7) was initiated 7 days after anti-CTLA-4 treatment. In two separate experiments (example below), anti-CTLA-4 resulted in 85% and 97% mean tumor growth inhibition (TGI). Delayed treatment with Dex at 1 mg/kg did not effect TGI mediated by anti-CTLA-4 (83% and 95% TGI), while Dex at 10 mg/kg resulted in a limited abrogation of the anti-tumor effect (78% and 91% TGI). When Dex (1 and 10 mg/kg) was given concurrently with anti-CTLA4 (5 mg/kg), the anti-tumor effect by anti-CTLA-4 was still retained at early time points (day 18) but ultimately resulted in a reversal of TGI and tumor outgrowth at 24 days. Dex treatment alone did not significantly effect tumor volume in any study. These data support the use of corticosteroids in the treatment of adverse events following anti-CTLA-4 immunotherapy.