Blockade of CD25 reduces regulatory T cell expansion and some manifestations of IL-2 mediated toxicity but does not improve anti-tumor efficacy in animal models of IL-2 immunotherapy

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Abstract High dose IL-2 (HD IL-2) is an approved treatment for melanoma and RCC that can result in long term disease remission, but is associated with severe adverse side effects. Adverse effects may be mediated by non-specific activation of cells expressing the high affinity CD25-containing IL-2 receptor. HD IL-2 also results in the expansion of regulatory T cells (Treg) that may negatively impact tumor immunotherapy. Blocking IL-2 binding to CD25 was explored as a mechanism to reduce expansion of Tregs and adverse effects. We created a high affinity anti-mouse CD25 mAb that effectively blocks the interaction of IL-2 with CD25 and carries the N297A Fc region modification to reduce FcgR binding. Saturation of CD25 ameliorates some but not all biomarkers of IL-2 toxicity. These include behavioral signs and serum ALT elevation. However, lung and spleen weight increase induced by IL-2 was not affected by CD25 blockade. CD25 blockade reduced IL-2 mediated expansion of Tregs. A saturating dose of CD25 antibody prior to 5-6 days of IL-2 therapy resulted in a complete loss of IL-2-mediated tumor efficacy in the CT26 model. CD25 blockade and IL-2 expanded CD8+ and NK cells while reducing blood and TIL Tregs, but did not impact primary tumor growth in the 4T1 or B16F10 tumor models. The loss of anti-tumor activity in the CT26 model correlated with reduced CD8+ CD25+ expansion in the blood and the TIL populations. Expansion of CD25 negative CD8+ and NK cells with concomitant Treg cell suppression in three different syngeneic tumor models did not result in improved anti-tumor efficacy. This result has implications for IL-2 and IL-15 engineering, and suggests that IL-2 mediated toxicity cannot be completely controlled by re-directing IL-2 to the CD122/CD132 receptor.