Abstract
New combination immunotherapies are displaying both efficacy and immune-related adverse events (irAE) in humans. However, grade 3/4 irAEs occur in a high proportion, which can lead to discontinuation of treatment and can result in fatalities if not promptly treated. Prolonged T regulatory cell (Treg) depletion in tumor-bearing Foxp3-DTR mice using diphtheria toxin (DT) mirrored the spectrum of antitumor responses and severity of irAEs that can occur in ipilimumab/nivolumab-treated patients. In contrast, transient Treg depletion or anti-CTLA-4/PD-1 therapy had equivalent effects in mice, lowering the immune tolerance threshold and allowing irAEs to be more easily induced following treatment with additional immunomodulatory antibodies. Transient Treg depletion of DT in combination with anti-PD-1 or anti-TIM-3 monoclonal antibodies had a high therapeutic window compared with DT plus anti-CD137. In contrast, DT plus anti-CD137-treated mice developed severe irAEs similar to grade 3/4 clinical symptoms. These irAEs appeared because of an infiltration of activated proliferating effector T cells in the tissues producing IFNγ and TNF; however, TNF blockade decreased irAEs severity without impacting on tumor growth. Cancer Res; 76(18); 5288-301. ©2016 AACR.
Highlights
The combination of ipilimumab [anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4)] and nivolumab [anti-programmed cell death protein 1 (PD-1)] to target T-cell checkpoint receptors in the treatment of advanced melanoma has produced rapid and impressive anticancer effects [1, 2] and may result in significant efficacy against other cancers
Using the Foxp3-DTR mice, we asked how transient (1 dose diphtheria toxin (DT)) or prolonged (2 or 5 doses DT) T regulatory cell (Treg) depletion impacted on tumor growth and development of autoimmune toxicity
Having optimized the dose of DT required to maximally deplete Tregs (Supplementary Fig. S1), we determined how transient or prolonged Treg depletion in BALB/c or C57BL/6 Foxp3-DTR mice affected tumor growth in 4 different tumor models (Fig. 1)
Summary
The combination of ipilimumab [anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4)] and nivolumab [anti-programmed cell death protein 1 (PD-1)] to target T-cell checkpoint receptors in the treatment of advanced melanoma has produced rapid and impressive anticancer effects [1, 2] and may result in significant efficacy against other cancers. These clinical data, together with results from preclinical mouse tumor models, demonstrate that multiple immunosuppressive pathways exist in tumors and that their cotargeting can increase the efficacy of host antitumor.
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