Phase I clinical experience of a targeted TCR-IL2 fusion protein in patients with metastatic malignancies

Abstract

3040 Background: ALT-801 is recombinant human interleukin-2 (IL-2) genetically fused to a single-chain T-cell receptor specific to a peptide antigen of human p53 presented in the context of HLA-A2 positivity. In tumor xenografts in animal models, this fusion protein demonstrated potent and targeted antitumor activity. Methods: A phase I/IIa multicenter clinical study was initiated to assess safety and clinical response of ALT-801 in patients with various metastatic malignancies. Patients screened positively for HLA-A2 and tumors expressed p53 peptide/HLA-A2 complex. In this dose escalation trial, patients received ALT-801 as a daily intravenous infusion for 4 days followed by a 10-day rest period and 4 additional daily doses. Results: Data from three dosing cohorts (0.015, 0.04, and 0.08 mg/kg/dose) indicate that ALT-801 is well-tolerated up to 0.04 mg/kg/dose. The half-life of ALT-801 is 2.5–4 hours per pharmacokinetic analysis, depending on the dose. Even at the 0.015 mg/kg level, there were sufficient concentrations of ALT-801 in the patients’ serum to fully activate cell lytic activity in vitro. Treatment with ALT-801 also led to immune activation in patients as demonstrated by elevated serum IFN-γ levels as well as an increase in IFN-γ-producing immune cells in patients’ blood. Interestingly, serum TNF-α, a major inducer of hypotension in patients receiving high-dose IL-2 treatment, was not induced in patients receiving ALT-801. Evidence of antitumor activity (i.e., stable disease, tumor shrinkage) was observed in some patients after one or two courses of ALT-801. Conclusions: At a dose of 0.04 mg/kg, ALT-801 is a well-tolerated agent that generated a vigorous immune response and demonstrated clinical efficacy in a group of patients with various metastatic malignancies. An expansion cohort of patients is in progress at 0.04 mg/kg. [Table: see text]