Remarkable tumor lysis in a hepatocellular carcinoma patient immediately following glypican-3-derived peptide vaccination
A 62-year-old male had a history of asymptomatic chronic hepatitis C. In September 2009, he was diagnosed with HCC. Laboratory data disclosed no abnormalities. Abdominal CT (CT) scans showed four lesions in the liver, and the patient was treated four times with hepatic artery chemoembolization. In December 2010, CT scans revealed a new lesion indicative of a tumor thrombus extending into the inferior vena cava. The patient was treated with sorafenib. However, the sorafenib treatment was discontinued in January 2011 due to progressive multiple intrahepatic tumors.\nAs no established therapeutic regimens exist for this condition, he was offered participation in a clinical trial of a GPC3 peptide vaccine for advanced HCC. HLA-typing revealed an HLA-A2 phenotype. The patient had a performance status of 0, and Child-Pugh class B disease. The patient did not have active HBV infection or rapidly progressive tumor thrombus before enrollment, met the eligibility criteria, and was enrolled after providing informed consent. Early-phase contrast-enhanced CT before treatment showed a maximum 68 × 51-mm tumor with multiple intrahepatic tumors and a 44 × 30-mm tumor invading the right atrium (). Pretreatment tumor markers were as follows: α fetoprotein (AFP), 852 ng/mL and des-gamma-carboxy prothrombin (DCP), 1346 mAU/mL. A liver biopsy was performed 1 week prior to GPC3 peptide vaccination according to the protocol. In April 2011, 3 mg of HLA-A2-restricted GPC3144-152 peptide (FVGEFFTDV) (American Peptide Co.) emulsified with incomplete Freund’s adjuvant (Montanide ISA-51VG; SEPPIC) was injected intradermally as the vaccine following Good Manufacturing Practice guidelines. The patient had a low-grade fever on day 6 following the first vaccination, and inflammatory and hepatic parameters were elevated on day 12 (). The abnormal laboratory findings improved later. Therefore, he received the second vaccination on day 26 after the first vaccination. On day 9 after the second vaccination, the patient was admitted to our hospital with a high fever and general fatigue. On admission, the patient’s C-reactive protein (CRP) level (10.76 mg/dL) and laboratory hepatic parameters were elevated. One day after hospitalization, aspartate aminotransferase and alanine aminotransferase and levels were elevated to 1,580 IU/L and 1,112 IU/L, respectively. The prothrombin time-international normalized ratio increased from 1.18 to 1.51. But the patient did not have ammonemia or asterixis. As seen by early-phase contrast-enhanced CT scan, most tumors in the liver were not contrast enhanced. Findings of the CT scan indicated tumor necrosis and regression. In contrast, the size of the tumor thrombus in the right atrium increased to a maximum of 83 × 50 mm (). Levels of the tumor markers AFP and DCP decreased temporarily to 634 ng/mL and 777 mAU/mL, respectively. He was infused with a liver-supporting agent (monoammonium glycyrrhizinate, glycine, and l-cysteine hydrochloride hydrate). The inflammatory and hepatic parameters improved 1 week after hospitalization (). We did not perform a liver biopsy when the hepatic parameters were elevated because they improved promptly. Nevertheless, his status worsened gradually. Protocol treatment was discontinued due to progressive disease and he died 30 days after the second vaccination. Based on the clinical course, we could not rule out the possibility that his condition had worsened as a result of the vaccine. Therefore, an autopsy was performed to determine the main cause of death and the elevated hepatic parameters, and to evaluate the anti-tumor effect of vaccination