A Phase II Trial of PT-112 in Subjects with Thymoma and Thymic Carcinoma

Division Of Basic Sciences - Nci

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Abstract

PT-112 is a small molecule inhibitor of ribosomal biogenesis that induces immunogenic cell death and activates an anti-cancer immune response. In pre-clinical studies, PT-112 increases immune cell infiltration into tumor tissue, with an increase in CD8+ T cells, decrease in FOXP3+ regulatory T cells, and an increase in the CD8+ T cell/Treg ratio. In the ongoing phase II study of PT-112 in recurrent thymic epithelial tumors, clinical activity has been observed with an objective response or disease stability seen in 82% of evaluable participants. Treatment is well tolerated. The most common treatment-related adverse events are anemia, thrombocytopenia, fatigue and peripheral neuropathy. One participant experienced new-onset immune-mediated myositis which was successfully treated with high-dose steroids. Two participants experienced a relapse of previously diagnosed paraneoplastic autoimmunity: ocular myasthenia (CRMP5 and CASPR2 antibody-positive) and immune cytopenia. Analysis of peripheral blood mononuclear cells showed increases in proliferative and NKp46+ (activating receptor) Natural Killer cells, proliferative CD4+ and CD8+ T cells, and PD-L1+ monocytes, as well as a decrease in naive CD4+ T cells. Analysis of serum cytokines and soluble factors from a subset of patients showed an increase in proinflammatory cytokines interferon (IFN)-g and tumor necrosis factor (TNF)-a and decreases in immunosuppressive factors vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-b1. Pooled results from available pre- and on-treatment tumor biopsies show an increase in immune cell density and increase expression of IFN-g after beginning PT-112 therapy. Multiplex immunofluorescence analysis of a resected pleural metastasis from a participant with type B3 thymoma obtained at progression occurring 16.5 months after initiating PT-112 therapy and 12.5 months after PT-112 discontinuation with no subsequent therapy revealed an increase in stromal M2 macrophage density and the M2/M1 ratio, as well as increases in CD8+ T cells and NK cells in both tumor and stroma compared with a previous on-treatment biopsy. Taken together, these results show that treatment with PT-112 induces robust signals of immune activation across the adaptive and innate immune systems. These results are consistent with prior pre-clinical findings and are indicative of PT-112's immunomodulatory effects underlying its anti-cancer activity.