Association Between High-Avidity T-Cell Receptors, Induced by α-Fetoprotein−Derived Peptides, and Anti-Tumor Effects in Patients With Hepatocellular Carcinoma
2017
Background & Aims Levels of α-fetoprotein (AFP) are measured for surveillance and diagnosis of hepatocellular carcinoma (HCC). We performed a phase 1 trial to evaluate the safety and efficacy of AFP-derived peptides as an anti-tumor vaccine for patients with advanced HCC, and characterized induction of AFP-specific T-cell receptors (TCRs). Methods We performed a prospective study of 15 patients with HCC seen at Kanazawa University Hospital in Japan from March 2010 through March 2012. Each patient was given a subcutaneous injection of 3 mg AFP-derived peptides (AFP 357 and AFP 403 ) in an emulsion with incomplete
Freund's adjuvantevery other week for at least 6 weeks. Patients were evaluated every 8 weeks by radiologic imaging; adverse events and toxicities were categorized and graded using the
common terminology criteriafor
adverse events. Criteria for discontinuation included unacceptable toxicities and disease progression defined as progressive disease using the
Response Evaluation CriteriaIn
Solid Tumorscriteria. Patients' immune responses were monitored using an interferon-gamma enzyme-linked immunospot assay. Peptide-specific TCRs were assessed using a rapid TCR cloning and evaluation system. The observation period was 730 days. A complete response was defined as the disappearance of all tumors; stable disease was defined as tumors whose total diameter remained between >70% and Results We did not observe any serious adverse reactions to the peptides, which were well tolerated. Of the 15 patients who received at least 3 injections, 5 (33%) had an immune response to the peptides. One of the 15 patients had a complete response and disease stabilized in 8 patients. In 4 of the 15 patients, we detected AFP 357 -specific CD8 T cells; we cloned 14 different TCRs with different
aviditiesfor the peptide. A TCR with the highest
aviditywas observed in the patient who achieved a complete response for more than 2 years. Conclusions In a phase 1 trial, administration of AFP-derived peptides to 15 patients with HCC did not cause adverse events and produced T cells with receptors that reacted to the peptides; 1 patient had a complete response and tumor growth slowed in 8 patients. T cells from the patient with a complete response expressed a highly functional TCR induced by the
peptide vaccines. UMIN-CTR no: UMIN000003514.
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