Currently available therapeutic drugs for chronic hepatitis B virus (HBV) infection include interferon-α (INF-α) and or nucleos(t)ide analogs. However, INF-α treatment is limited by its relatively low response (30-40%) rate and deleterious effects, while nucleos(t)ide analogue treatment is limited by the need for long-term therapy and the development of mutant drug resistance. Thus application of immunotherapy to treatment of chronic HBV infection has gained popularity due to a better understanding of how to activate antiviral immune response.
Therapeutic vaccines provide a useful method for triggering immune responses. In a model of HBV transgenic mice, hepatitis B therapeutic vaccines have been reported to elicit HBV-specific cytotoxic T lymphocyte (CTL) responses and control HBV replication. In clinical trial, HBV core antigen peptide 18-27 (HBc18-27) has been shown to induce significant HBV-specific CTL response in healthy subjects. Alternatively, several clinical trials have demonstrated that adoptive transfer of HBV-immune memory T cells from an immune donor through bone marrow transplantation (BMT) or transfer of peripheral blood lymphocytes (PBL) can induce serological clearance of the HBsAg and lead to seroconversion in patients with CHB. However, allogeneic BMT treatment is restricted to BMT setting and limited by its potential serious complications. In this respect, administration of autologous, multi-factors activated, HBV-specific CTL is thought to be another practical therapeutic option for CHB patients. These cells may be harvested from patients’ peripheral blood, expanded in vitro and reinfused to eradicate HBV in vivo. In clinical trials, adoptive transfer of these cells was well-tolerated in CHB patients and showed strong anti-viral efficacy, even if antiviral drug resistance has developed. Improved CTL cell culture technology can further enhance the antiviral function of adoptively transferred T cells. Current strategies for augmenting the function of cultured T cells have focused on cytokines, co-stimulatory molecules and immune checkpoint that regulate proliferation, survival, activation and differentiation of T cells.
However viruses have evolved numerous immunosuppressive mechanisms to escape the immune attack. In patients with chronic HBV infections, functions of both DCs and CTLs are inhibited by high HBV load, leading to the limited efficacy of therapeutic vaccines. Therefore, as a corollary, the strategy of therapeutic viral vaccination of CHB patients is likely to succeed mainly in the setting of low HBV load. On the contrary, although adoptive transfer of in-vitro expanded CTL may be superior to therapeutic vaccination as a single therapeutic modality against HBV and may directly contribute to the reduction of HBV load, most of the CTL responses may be transient and the patients may have limited persistence of these transferred cells. Moreover, the tolerizing microenvironment of liver further impair the effectiveness of immunotherapy. Hence, better understanding of the mechanisms of HBV immunotolerance will improve the success of future therapies. In addition, it will be interesting to investigate if combination of therapeutic vaccines and adoptive T cell transfer can be used to achieve off-treatment sustained suppression of HBV replication and remission of liver disease. Furthermore, selection of suitable candidates for immunotherapy and identification of biomarker of response seems to be paramount.