Alterations in Hepatocellular Carcinoma-Specific Immune Responses Following Hepatitis C Virus Elimination by Direct-Acting Antivirals.

Direct-acting antivirals (DAAs) have recently revolutionized the eradication of chronic hepatitis C virus (HCV) infection. However, the effects of DAAs on the development of hepatocellular carcinoma (HCC) remain unknown. Therefore, the present study aimed to investigate immune responses to HCC influenced by DAAs in HCV-infected patients and elucidate the underlying mechanisms. We compared immune responses to 19 different HCC-related tumor-associated antigen (TAA)-derived peptides and host immune cell profiles before and 24 weeks after a treatment with DAAs in 47 HLA-A24-positive patients. The relationships between the different immune responses and phenotypic changes in immune cells were also examined. The treatment with DAAs induced four types of immune responses to TAAs and markedly altered host immune cell profiles. Prominently, reductions in the frequencies of PD-1+CD4+ and PD-1+CD8+ T cells by DAAs were associated with enhanced immune responses to TAAs. The HCV F protein was identified as contributing to the increased frequency of PD-1+ T cells, which may be decreased after eradication by DAAs. DAAs altered the immune responses of patients to HCC by decreasing the frequency of PD-1-expressing CD4+ and CD8+ T cells.

Multiple therapeutic peptide vaccines for patients with advanced gastric cancer.

We performed a clinical trial using HLA-A24-binding peptide vaccines containing a combination of novel cancer-testis antigens and anti-angiogenic peptides for advanced gastric cancer (GC). Thirty-five GC patients who had shown resistance to the standard therapy were enrolled in this clinical trial using vaccinations with a mixture of multiple peptides derived from DEPDC1, URLC10, FoxM1, Kif20A and VEGFR1. The safety, the overall survival (OS), and the immunological responses based on an ELISPOT assay were determined to assess differences in patients who were HLA-A24-positive [24(+)] and HLA-A24-negative [24(-)]. No severe adverse effects were observed except for severe skin reactions in 4 patients. The differences in OS were not significant between patients who were 24(+) and 24(-). In the 24(+) group, patients who showed T cell responses specific to antigen peptides had a tendency towards better survival than those who showed no response, especially to the DEPDC1 peptide. The patients with local skin reactions had significantly better OS than the others. Peptide vaccine therapy was found to be safe and is expected to induce specific T cell responses in patients with advanced GC. The survival benefit of peptide vaccine monotherapy may not have been shown and further trials are needed to confirm these results.

Phase I/II clinical trial using HLA-A24-restricted peptide vaccine derived from KIF20A for patients with advanced pancreatic cancer.

BACKGROUND: We previously developed an immunotherapy treatment utilizing a cancer vaccine reagent KIF20A-66 in order to treat pancreatic cancer. KIF20A-66 is HLA-A24-restricted epitope peptide derived from KIF20A, a member of kinesin super family protein 20A that is significantly transactivated in pancreatic cancer. In this report, we further demonstrated non-randomized, open-label, single centered phase I/II clinical trial of immunotherapy using the KIF20A-66 peptide for the patients with advanced pancreatic cancer. METHODS: Vaccination was performed to the patients with metastatic pancreatic cancer, in whom gemcitabine-based therapy had failed. In phase I study, KIF20A-66 peptide was subcutaneously injected weekly in a dose-escalation manner (doses of 1.0 and 3.0 mg/body, 6 patients/1 cohort). After safety was assessed, phase II study was conducted using 3.0 mg of KIF20A-66 peptide. RESULTS: KIF20A-66 peptide vaccination was well tolerated in the doses we examined and tumor responses after 1 month of the treatment were evaluated. Among 29 patients who completed one course of the treatment at least, stable disease (SD) was found in 21 cases, while progressive disease (PD) was found in 8 cases, indicating that the disease control rate was 72%. Objective tumor shrinkage was observed in 8 cases, including 1 case of complete response (CR). The median survival time (MST) and progression free survival time (PFS) were 142 days and 56 days, respectively. These results clearly demonstrate that overall survival of the patients was significantly prolonged, compared to the historical controls of 9 cases with unmatched HLA in the same hospital (MST: 83 days), as well as 81 cases in our and other hospitals (MST: 63 days). CONCLUSION: The patients vaccinated with KIF20A-66 peptide had better prognosis than the control group with best supportive care (BSC). Thus, we concluded that KIF20A-66 vaccination is significantly effective as an immunotherapy against advanced pancreatic cancer. KIF20A-66 peptide was well tolerable in the dose of either 1.0 mg or 3.0 mg/body, and effectively induced peptide-specific response of cytotoxic T lymphocyte (CTL). Further clinical study using this peptide is a promising approach for advanced pancreatic cancer to achieve high potential benefit for better prognosis. CLINICAL TRIAL REGISTRATION: UMIN-CTR, number UMIN000004919.