Systemic administration of anti-4-1BB agonistic antibody at doses of as little as 200 μg/mouse has been shown to cause splenomegaly and other immune system anomalies [30], therefore it is essential to determine the important targets of anti-4-1BB for tumor control so that more focused therapies can be devised to potentially avoid immunotoxicity. This evidence concerns the gene TNFRSF9 and Splenomegaly.