Targeting CD70 in cutaneous T-cell lymphoma using an antibody-drug conjugate in patient-derived xenograft models

Abstract

CD70 is a member of the tumor necrosis factor (TNF) receptor superfamily. Emerging data indicate that CD70 may be a suitable target for various malignancies. We investigated the expression of CD70 in cutaneous and systemic T cell lymphomas; and conducted pre-clinical studies of SGN-CD70A, a CD70-directed antibody-drug conjugate, using patient-derived cutaneous T cell lymphoma (CTCL PDX) models. CD70 expression was examined by immunohistochemical stains in 46 diagnostic specimens of T cell lymphomas. The activities of SGN-CD70A in growth inhibition and apoptosis induction were examined in CTCL cell lines and primary CTCL tumor cells. Using previously established CTCL PDXs, we conducted a dose-finding trial, followed by a phase II-like trial, to evaluate the optimal dosing and the efficacy of SGN-CD70A in tumor-bearing PDX animals. The therapeutic efficacy of SGN-CD70A was measured by tumor-associated cell-free DNA (cfDNA) and survival of treated PDXs. We found that CD70 is highly expressed in T cell lymphomas, especially in CTCL. SGN-CD70A inhibited cell growth and induced apoptosis in CD70-expressing CTCL cell-lines and primary tumors cells. Additionally, SGN-CD70A at 100 µg/kg and 300 µg/kg prolonged survival of PDXs in a dose-dependent manner. Finally, treatment with three doses of SGN-CD70A at 300 µg/kg was superior to single dose treatment in survival prolongation (median survival: 111 days vs. 39 days, p=0.017). Most importantly, multiple-dosing of SGN-CD70A induced complete eradication of established tumors in PDXs measured by cfDNA. Our results demonstrated marked anti-tumor activity of SGN-CD70A in CTCL PDXs, providing compelling support for its clinical investigation.