PURPOSE Tumor-associated antigen cytotoxic T cells (TAA-Ts) represent a new, potentially effective and nontoxic therapeutic approach for patients with relapsed or refractory solid tumors. In this first-in-human trial, we investigated the safety of administering TAA-Ts that target Wilms tumor gene 1, preferentially expressed antigen of melanoma, and survivin to patients with relapsed/refractory solid tumors. MATERIALS AND METHODS TAA-T products were generated from autologous peripheral blood and infused over three dose levels: 1, 2, and 4 × 107 cells/m2. Patients were eligible for up to eight infusions administered 4 to 7 weeks apart. We assessed dose limiting toxicity during the first 45 days after infusion. Disease response was determined within the context of a phase I trial. RESULTS There were no dose-limiting toxicities. Of 15 evaluable patients, 11 (73%) with stable disease or better at day 45 postinfusion were defined as responders. Six responders remain without progression at a median of 13.9 months (range, 4.1 to 19.9 months) after initial TAA-Ts. Patients who were treated at the highest dose level showed the best clinical outcomes, with a 6-month progression-free survival of 73% after TAA-T infusion compared with a 38% 6-month progression-free survival with prior therapy. Antigen spreading and a reduction in circulating tumor-associated antigens using digital droplet polymerase chain reaction was observed in patients after TAA-T infusion. CONCLUSION TAA-Ts safely induced disease stabilization, prolonged time to progression, and were associated with antigen spreading and a reduction in circulating tumor-associated antigen DNA levels in patients with relapsed/refractory solid tumors without lymphodepleting chemotherapy before infusion. TAA-Ts are a promising new treatment approach for patients with solid tumors.

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Fanconi anemia (FA), a genetic disorder affecting DNA repair, is characterized by bone marrow failure and cancer susceptibility. In FA mouse models the biguanide metabolic agent metformin improves blood counts and delays tumor development. We conducted a single institution pilot study of metformin in non-diabetic patients with FA to assess feasibility and tolerability of metformin treatment and to determine whether metformin could improve blood counts. Fourteen of 15 patients with at least 1 cytopenia (hemoglobin <10g/dL, platelet count <100K cells/µL, or an absolute neutrophil count <1K cells/µL) were eligible to receive metformin for 6 months. Median patient age was 9.4 years (range 6.0-26.5), and 8/14 were male (57%). Thirteen of 14 subjects (93%) tolerated maximal dosing for age; one subject had dose reduction for grade 2 gastrointestinal symptoms. No subjects developed hypoglycemia or metabolic acidosis. No subjects had dose interruptions due to toxicity, and no grade 3 or higher adverse events attributed to metformin were observed. Hematologic response (HR) based on modified MDS IWG criteria was observed in 4 of 13 evaluable patients (30.8%, 90% CI:11.3 to 57.3). Median time to response was 84.5 days (range 71-128). Responses were noted in neutrophils (n=3), platelets (n=1), and red blood cells (n=1). No subjects met criteria for disease progression or relapse during treatment. Correlative studies explored potential mechanisms of metformin activity in FA. Plasma proteomics showed reduction in inflammatory pathways with metformin. We conclude that metformin is safe and tolerable in non-diabetic patients with FA and may provide therapeutic benefit. This trial is registered at www.clinicaltrials.gov as NCT03398824.