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Aim: We aimed to further investigate the role of hepcortespenlisimut-L (Hepko-V5 or V5), a new oral immunotherapy developed by us, for hepatocellular carcinoma (HCC) indication. Methods: The interim data from ongoing Phase Ⅲ placebo-controlled, randomized trial were evaluated on the initial group of patients in advanced stage of HCC with emphasis on liver function and tumor marker alpha-fetoprotein levels. Additionally, an in vitro study was undertaken to elucidate the mechanism of action of V5 by measuring with flow cytometry the expression of cytokines such as IL-2, INF-γ, and TNF-α and cell activation markers CD69 and Ki67 on CD4- and CD8-positive lymphocytes isolated from peripheral blood of healthy volunteers. Results: As early as one month after treatment initiation, there was a clear improvement in alanine transaminase, aspartate transaminase, alkaline phosphatase, and bilirubin levels among HCC patients who received daily dose of V5, but not in the placebo group. Additionally, alpha-fetoprotein (AFP) levels among V5 recipients decreased, while in the placebo group they rose. Clinical results are in line with in vitro observations indicating immune activation, as evidenced by many-fold enhancement of CD69, Ki67, and INF-γ expression and at the same time marked anti-inflammatory effect resulting in 10-fold decrease in TNF-α output and lack of influence on IL-2 production.Conclusion: Hepcortespenlisimut-L, a tableted oral formulation derived from heat-inactivated pooled blood of patients with HCC and viral hepatitis shows beneficial clinical effect, as demonstrated by improvement in liver function and reduction of tumor marker AFP levels. These correlate with in vitro observations showing potent activation of the immune response and pronounced oral tolerance effect.