肝细胞癌免疫治疗的现状及发展

肝癌是一种严重的全球健康问题,也是常见的癌症相关死亡原因。肝细胞癌(hepatocellular carcinoma,HCC)是肝癌常见的病理类型。早期HCC临床症状不明显,50%的HCC患者确诊时已处于晚期。系统全身治疗被推荐用于晚期HCC。随着分子靶向药物(索拉非尼、仑伐替尼)的发展,晚期HCC的系统全身治疗取得了一定进展,但对HCC患者生存获益仍然不大。近年来,免疫检查点抑制剂的出现改变了HCC治疗的格局,为HCC精准治疗提供了更多的可能性并展现出较好的效果。特别是阿替利珠单抗和贝伐珠单抗的联合疗法显著改善了HCC患者的生存预后,此外,过继性细胞疗法、肿瘤疫苗、溶瘤病毒和非特异性免疫治疗也已成为免疫治疗策略。本文就HCC免疫治疗的现状及发展进行概述。

Fixed-Tumor Vaccine: A Practical Formulation with Cytokine-Microspheres for Protective and Therapeutic Antitumor Immunity

Objective: To study the protective and therapeutic antitumor immunity against hepatocellular carcinoma (HCC) with the fixed-tumor vaccine.Methods: A tumor vaccine consisting of fixed tumor cells or fixed tumor fragments combined with sustained-releasers of cytokines and a non-toxic adjuvant was developed. C57BL/6J mice were immunized intra-dermally with the vaccine on day 0 and 7, followed by intrahepatic challenge with live Hepa 1–6 cells.Results: All of 15 nonimmunized control mice developed the hepatoma. Protection of mice immunized with fixed Hepa 1–6 cells and both of IL-2/GM-CSF microspheres or further mixed with TiterMax Gold reached 80% and 87%, respectively. Mass growth of the established tumors, vaccinated twice at 5 mm in diameter, the tumor of control animals continued to grow. However, 7–10 days after the second injection of the tumor vaccine, the tumor growth was suppressed in 9 of 10 mice and then markedly reduced. Complete tumor regression was observed in 60% (6/10) of mice. Splenocytes from the control mice were not able to lyse target Hepa 1–6 cells and other tumor cells. In contrast splenocytes from the vaccinated mice exhibited a 41% lytic activity against the Hepa 1–6 cells tested at an effector/target (E/T) ratio of 5, whereas they did not exhibited such activity against the melanoma cells (B16-F1), Lewis lung carcinoma cells (LLC), renal carcinoma cells (Renca), and bladder carcinoma cells (MBT-2). The cytotoxic activity was inhibited by the treatment with anti-CD3, anti-CD8, and anti-MHC-class I monoclonal antibodies but not with anti-CD4 and anti-MHC-class II antibodies. In the Phase-I clinical trial, vaccination of HCC patients with the autologous vaccine is a well-tolerated treatment and induces fixed tumor fragment-specific immunity.Conclusion: Fixed HCC vaccination elicited protective and therapeutic antitumor immunity against HCC. The tumor vaccine elicited antigen specific CTL response lysis of the target HCC was mediated by the typical MHC-class I restricted CD8+ T cells. Key words cancer vaccine - cytotoxic T lymphocyte - immunotherapy - hepatoma

Significance of changes in local immunity in patients with hepatocellular carcinoma after percutaneous microwave coagulation therapy

OBJECTIVE: To assess the local immune response in patients with hepatocellular carcinoma after percutaneous microwave coagulation therapy (PMCT). METHODS: Seventy-eight patients with hepatocellular carcinoma underwent PMCT. Both cancerous and adjacent liver tissue were taken before, and 3, 17 and 30 days after PMCT using ultrasound-guided liver biopsy. Specimens were stained by immunohistochemical techniques for detecting CD3, CD45RO, CD56, CD68, and CD20 positive cells. RESULTS: A few CD3, CD45RO, CD56, CD68 and CD20 positive cells were observed in the cancer stroma and surrounding sinusoids in liver tissue pre-PMCT. The number of immunocytes, except for CD20 positive cells, was significantly increased both within the cancer and the adjacent liver tissue, with a larger increase in tumor tissue at day 3 post-PMCT compared with pre-PMCT. These immunocytes were enlarged in size. The number of CD3, CD45RO and CD56 positive cells peaked at day 17 and CD68 positive cells peaked at days 3 post-PMCT. At day 30 post-PMCT, this increase still existed. These infiltrating immunocytes distributed in the parenchyma of the tumor, and within the lumen of small blood vessels after PMCT. In addition, more infiltrated immune cells were seen in cancer cell spaces. CONCLUSIONS: A change in immunocyte infiltration takes place in number, configuration and location after patients with HCC are treated with percutaneous microwave coagulation, suggesting that local immune function is enhanced post-PMCT.

Anti-hepatocarcinoma activity of TT-1,an analog of melittin,combined with interferon-α via promoting the interaction of NKG2D and MICA

Hepatocarcinoma is one of the malignant cancers with significant morbidity and mortality.Immunotherapy has emerged in clinical treatment,owing to the limitation and severe side effects of chemotherapy.In the immune system,natural killer（NK）cells are important effectors required to eliminate malignant tumor cells without the limitation of major histocompatibility complex（MHC）molecule issues.Hence,treatment which could stimulate NK cells is of great interest.Here,we investigated the efficacy of the combined therapy of TT-1（a mutant of melittin）and interferon-α（IFN-α）on NK cells and human liver cancer HepG-2/Huh7 cells in vitro and in vivo,as well as the mechanism involved.The combination therapy significantly inhibited the growth of HepG-2/Huh7 cells in vivo,but this effect was impaired after depleting NK cells.TT-1 not only up-regulated MHC class I-related chain molecules A（MICA）expression,but also prevented the secretion of soluble MICA（sM ICA）.Both the mR NA and protein of a disintegrin and metallopeptidase 10（ADAM 10）in HepG-2/Huh7 cells were decreased after TT-1 treatment.The combined therapy of TT-1 and IFN-αcould suppress the growth of HepG-2/Huh7 xenografted tumor effectively via promoting the interaction of NK group 2,member D（NKG2D）and MICA,indicating that TT-1＋IFN-αwould be a potential approach in treating liver cancer.