Phase I Study of Chimeric Antigen Receptor Modified T Cells in Patients with EGFR-positive Advanced Biliary Tract Cancers

Purpose: This study is an expanded and parallel clinical trial of epidermal growth factor receptor (EGFR)-specific chimeric antigen receptor-engineered autologous T (CART) cell immunotherapy (NCT01869166) to assess the safety and activity of CART-EGFR cell therapy in EGFR-positive advanced unresectable, relapsed/metastatic biliary tract cancers (BTCs). Patients and Methods: Patients with EGFR-positive (>50%) advanced unresectable, relapsed/metastatic BTCs were enrolled. Well produced CART-EGFR cells were infused in a manner of dose escalation after the conditioning treatment with nab-paclitaxel (100-250 mg/m2) and cyclophosphamide (15-35 mg/kg). Results: A total of 19 patients (14 cholangiocarcinomas and 5 gallbladder carcinomas) received 1- to 3-cycles of CART-EGFR cell infusion (Median CART cell dose, 2.65 x 106kg, range, 0.8 to 4.1 x 106/kg) within 6 months. The CART-EGFR cell infusion was tolerated, but 3 patients suffered grade ≥ 3 acute fever/chill. Grade 1/2 target-mediated toxicities including mucosal/cutaneous toxicities and acute pulmonary edema and grade ≥ 3 lymphopenia and thrombocytopenia related to the conditioning treatment were observed. Of 17 evaluable patients, 1 achieved complete response and 10 achieved stable disease. The median progression-free survival was 4 months (range, 2.5 months to 22 months) from the first cycle of treatment. Analysis of data indicated the enrichment of central memory T cells (Tcm) in the infused CART-EGFR cells improved the clinical outcome. Conclusion: The CART-EGFR cell immunotherapy was a safe and active strategy for EGFR-positive advanced BTCs. The enrichment of Tcm in the infused CART-EGFR cells could predict clinical response.

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