Liver cancer is the most common type of hepatic malignancies, with poor prognosis. Treatment for Liver cancer are limited, especially for patients with advanced disease who are not eligible for curative hepatectomy or hepatic transplantation. Here The immunotherapy strategies for Liver cancer are reviewed, and Vaccines, adaptive therapy, immune checkpoint blockades and cytokines are included.
A large body of vaccines have been under research, including AFP targeted vaccine, glypican-3 (GPC3) targeted vaccines, Cell-free vaccines based on AFP and GPC3 DNA vaccine, DC vaccines, Fusion antigen vaccines, AFP vaccine created by computer-guided methodical epitope-optimization, artificial genetic recombination vaccinia virus vaccine.
Cytokine-induced killer (CIK) cells are in vitro activated autologous and allogeneic T cells, which have acquired non-specific anti-tumor cytotoxicity and CD56 overexpression, and representing a cell population with double T and NK phenotype.Other approaches such as NK cells or Chimeric antigen receptor-T cells (CAR-T) is also considered as a potential treatment for solid tumor. NK cells were found involved in the anti-tumor effect in HCC xenograft mouse models. Although CAR-T therapy has been evaluated in the treatment of hematological malignancies such as lymphoid leukemia and acute myeloid leukemia, there is rare evidence for the application of CAR-T in liver cancer immunotherapy.
Tremelimumab is a monoclonal antibody that blocks CTLA-4. A phase II, non-controlled, multicenter clinical trial enrolled 21 patients with liver cancer and chronic HCV infection. nivolumab is fully human IgG4 monoclonal antibody targeting PD-1 receptor. An active phase I dose escalation clinical trial is now recruiting for liver cancer. In addition to PD-1 and CTLA-4, other potential checkpoints, like VISTA, OX40, TIM-3, LAG-3 and BTLA were under investigation. Preclinical studies have indicated anti-tumor activity of LAG3, TIM-3 and NK-inhibitory receptors, although efficacy and safety in liver cancer patients has not yet been reported. Studies on immune modulatory molecules such as CD244 (2B4), CD137 (4-1BB), and OX-40 are in progress. Immune checkpoint blockade therapy is considered to be a strategy with a bright future.
Cytokine therapy showed mediate response for treatment of liver cancer. Interferon (IFN) is used in the treatment of liver cance infection and also shows anti-tumor activity. Several randomized clinical trials on IFN have been completed with mixed results. Although liver cance patients may benefit from IFN, more attention should be paid on its side effect. Intratumoral application based on adenovirus-based approach may overcome these limitation. Chemokines are considered to regulate immune cell function by interacting with the receptors on the membrane. Tumor infiltrating immune cells, including T cells, NK cells and NKT cells, showed enhanced expression of certain receptors. Preclinical studies indicate that overexpression of certain chemokine genes, such as CXCL10 and CCL5 in liver cancer tissue predicted a better prognosis, which is correlated with CTL and NK cells. As we have discussed above, TGF-β is an immunosuppressor in liver cancer progression. There is a new cytokine targeting therapeutic approach, a novel small molecule inhibitor of TGF-b receptor I, LY2157299, is underinvestigation for liver cancer treatment.
Combination of immune checkpoint blockade such as PD-1/CTLA-4 antibody and other immunotherapy approaches will be a trend and acquire excellent clinical benefits. More translational studies and randomized, controlled trials are needed to promote the development of liver cancer immunotherapy.
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