First-in-human study of intravenous bispecific CTLA-4 × OX40 antibody (ATOR-1015) in advanced solid malignancies

BACKGROUND: Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), was the first approved checkpoint inhibitor; however, its use is hampered by treatment-related adverse events (TRAEs). ATOR-1015 is a bispecific antibody targeting CTLA-4 and OX40 designed to direct the effect to the tumor microenvironment and thereby improve the response rate and reduce TRAEs. MATERIALS AND METHODS: We conducted a phase I, first-in-human, multicenter study to determine the safety and tolerability of intravenously administered ATOR-1015 every second week. Secondary objectives were efficacy and pharmacokinetics. An exploratory objective was to investigate the pharmacodynamic effects on the immune system. Twenty-eight patients with advanced solid cancer were treated in the last line with ATOR-1015. A modified 3 + 3 dose-escalation design was applied. RESULTS: The most common TRAEs were infusion-related reactions (IRRs) (n = 14, 50.0%), pyrexia (n = 3, 10.7%), myalgia (n = 3, 10.7%) and rash (n = 3, 10.7%). One serious AE occurred (grade III IRR). Best response (according to immune RECIST) was stable disease (n = 11, 39.3%), which lasted >4 months in six patients (21.4%). These patients showed a significant increase in inducible T-cell costimulator-expressing CD4+ and CD8+ central memory T cells 4 h after infusion. In all patients, temporary elevations in absolute lymphocyte count, B cells and T cells as well as interleukin-8, interferon-γ and tumor necrosis factor-α were observed. CONCLUSIONS: Although considered safe, the treatment induced neutralizing anti-drug antibodies in most patients, leading to IRRs and reduced efficacy due to low serum exposure, an effect that could not be overcome by increasing doses. Future development requires re-engineering the therapeutic format to minimize immunogenicity, thereby improving both safety and effectiveness.