Abstract
e14587 Background: Immune checkpoint inhibitor (ICI) therapy has improved survival of patients with melanoma and other types of cancers. The effect of immunosuppresive corticosteroids on ICI efficacy is unknown, however treatment of immune-related adverse events with high-dose steroid therapy impairs neither efficacy nor time to failure of ICI. In certain clinical circumstances (for instance in the treatment of patients with symptomatic brain metastases) it may be advantageous to begin ICI therapy despite a requirement for steroid therapy. This study examined the effect of high-dose steroid therapy on lymphocyte proliferation/functionality after stimulation with anti-CD3 in the presence of pembrolizumab (PD-1 inhibitor) ex vivo. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from patients with either chronic hepatitis C infection or active malignant melanoma. CD4+ and CD8+ T cells were isolated and subjected to flow cytometry stating for the expression of PD-1. Isolated PBMCs were then pre-treated with prednisone (1 nM - 1 mM) before anti-CD3 stimulation. Anti-CD3-stimulated cells were then incubated with pembrolizumab (5 µg/mL) and their proliferative capacity and IL-2 secretion ability were measured by carboxyfluorescein succinimidyl ester (CFSE) staining and ELISA, respectively. Results: A dose-dependent inhibition of both lymphocyte proliferation and IL-2 production was observed, but at physiologically relevant nanomolar prednisone concentration the steroid effect was negligible. Millimolar prednisone concentrations resulted in > 50% relative reduction in lymphocyte proliferation, however even at this steroid concentration treatment with pembrolizumab was able to further stimulate proliferation and IL-2 secretion versus anti-CD3stimulation alone. Conclusions: Despite heavily immunosuppressive treatment, CD4+ and CD8+ lymphocytes demonstrate proliferative capacity and immunological activity following treatment with pembrolizumab. This suggests that treatment with pembrolizumab may be efficacious despite a requirement for steroid therapy, a scenario often encountered in patients with brain metastases.
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