Sequential Administration of Selinexor then CD19 CAR-T Cells Exhibits Enhanced Efficacy in a Mouse Model of Human Non-Hodgkin's Lymphoma

Abstract

Novel therapeutic approaches are urgently needed for many patients with Non-Hodgkin's Lymphoma (NHL). Approximately 30% of patients die within 5 years of diagnosis and many more relapse. Chimeric Antigen Receptor T cells (CAR-T) directed toward NHL antigens (e.g. CD19) are a promising new class of therapeutics for some patients with relapsed/refractory NHL, though a high percentage of patients (~50%) still fail to enter remission or relapse within one year of CD19 CAR-T therapy. Another approved therapeutic for treatment of a subtype of NHL patients is the nuclear export inhibitor, selinexor. Selinexor binds to exportin 1 and exhibits anti-tumor activity by impairing nuclear export of proteins including oncogenes and tumor suppressor proteins. As both CD19 CAR-T cells and selinexor exhibit activity against lymphoma cells, but suboptimal long term efficacy in patients, we assessed the combination of both treatments in a mouse model of NHL. The combinatorial efficacy was assessed using a circulating model of human NHL whereby RAJI-luciferase cells were intravenously injected into immunocompromised mice. Initial studies initiated treatment 7 days post tumor cell injection. Mice (n=5 NSG mice per cohort) were treated with selinexor alone (10mg/kg gavage 2x week) for study duration, CD19 CAR-T cells alone (single injection of 2.5x106 million cells) or a concurrent combination. Mice were imaged weekly for bioluminescence to monitor tumor progression. While CD19 CAR-T cells alone led to inhibition of tumor growth, there was no further enhancement in efficacy with the addition of concurrent treatment with selinexor (Figure 1A). Interestingly, when selinexor instead was administered only prior to CAR-T cell injection (10mg/kg gavage Day 1 and Day 3 post tumor cell injection followed by CAR-T injection Day 7 post tumor cell injection), there was a significant reduction in tumor burden in the combination group (Figure 1B). These results suggest that the tumor cells become sensitized to CD19 CAR-T mediated cell killing from selinexor administration. As both agents are FDA approved for certain NHL patients, this therapeutic strategy has high clinical relevance. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal