Phase I dose escalation safety and feasibility study of autologous WT1-sensitized T cells for the treatment of patients with recurrent ovarian cancer

Background: This phase I dose escalation trial evaluated the feasibility of production, safety, maximum tolerated dose, and preliminary efficacy of autologous T cells sensitized with peptides encoding Wilms' tumor protein 1 (WT1) administered alone or following lymphodepleting chemotherapy, in the treatment of patients with recurrent WT1⁺ ovarian, primary peritoneal, or fallopian tube carcinomas.

Methods: A 3+3 dose escalation design was used to determine dose-limiting toxicity (DLT). In cohort I, patients received WT1-sensitized T cells dosed at 5×10⁶/m² (level I) without cyclophosphamide lymphodepletion. In cohorts II-IV, patients received lymphodepleting chemotherapy (a single intravenous dose of cyclophosphamide 750 mg/m²), 2 days prior to the first intravenous infusion of WT1-sensitized T cells administered at escalating doses (2×10⁷/m² (level II), 5×10⁷/m² (level III), and 1×10⁸/m² (level IV)).

Results: Twelve patients aged 23-72 years, with a median of 7 prior therapies (range 4-14), were treated on the study. No DLT was observed, even at the highest dose level of 1×10⁸/m² WT1-sensitized T cells tested. Common adverse events reported were grade 1-2 fatigue, fever, nausea, and headache. Median progression-free survival (PFS) was 1.8 months (95% CI, 0.8 to 2.6); 1 year PFS rate 8.3% (95% CI, 0.5 to 31.1). Median overall survival (OS) was 11.0 months (95% CI, 1.1 to 22.6); OS at 1 year was 41.7% (95% CI, 15.2% to 66.5%). Best response was stable disease in one patient (n=1) and progressive disease in the others (n=11). We observed a transient increase in the frequencies of WT1-specific cytotoxic T lymphocyte precursors (CTLp) in the peripheral blood of 9 of the 12 patients following WT1-sensitized T-cell infusion.

Conclusion: We demonstrated the safety of administration of WT1-sensitized T cells and the short-term increase in the WT1 CTLp. However, at the low doses evaluated we did not observe therapeutic activity in recurrent ovarian cancer. In this heavily pretreated population, we encountered challenges in generating sufficient numbers of WT1-reactive cytotoxic T cells. Future studies employing WT1-specific T cells generated from lymphocytes are warranted but should be done earlier in the disease course and prior to intensive myelosuppressive therapy.

Trial registration number: NCT00562640.

One-sentence summary: The authors describe the first human application of autologous WT1-sensitized T cells in the treatment of patients with recurrent ovarian, primary peritoneal, and fallopian tube carcinomas.