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The possible mission of functional cure for HBV
HBsAg loss is regarded as a functional cure for HBV and serves as an ideal treatment endpoint. Nevertheless, it is rare to achieve the ultimate goal using current treatment modalities. There are several novel strategies to clear HBsAg, including killing of HBV-infected hepatocytes via cytotoxic T cell (CTL)-induced immunotherapy as the most promising one. Although HBV-specific CTL response is vigorous and multi-specific during acute HBV infection, it is usually weak or even undetectable during the CHB stage [26]. An ideal immune-therapeutic strategy should combine profound suppression of viral replication to prevent uninfected hepatocytes from HBV infection and restoration of HBV-specific CTL response to clear the infected hepatocytes. The former goal can be achieved by existing NA treatment and the later one could be partially enhanced by therapeutic vaccines [27]. To date, two clinical trials have been performed using different therapeutic vaccines to treat CHB patients with a similar strategy, yet the results of both have been disappointing [28, 29]; neither of the two therapeutic vaccines could clear HBsAg more effectively compared to the control group. There are two issues that must be considered. Firstly, HBV-specific CTL function has been shown to be preserved in children and young adults, but not in older patients [30]. Since both studies enrolled older patients, HBV-specific CTL response may fail to be triggered by therapeutic vaccinations. Second, the immune tolerant effects of the liver microenvironment must be considered. HBV-specific CTL response can be induced in peripheral blood, but is rapidly exhausted after the initiation of cytotoxic effects against HBV-infected hepatocytes (Fig. 1a,b). Either of the above issues may have led to the failure of the two clinical trials. If the failure was caused by the engagement of PD-1 on T cells and PD-L1 on hepatocytes, which leads to the inhibition of T cell receptor-mediated lymphocyte proliferation and cytokine secretion, an immune checkpoint inhibitor, such as anti-PD1, could be considered as an addition to the therapeutic vaccine for the amplification of these effects (Fig. 1c). Indeed, the success of this combination strategy has been demonstrated in a woodchuck model [31]. Although the current results of immunotherapy in CHB treatment are unsatisfactory, it remains the most attractive method to clear the virus as long as the appropriate patient population can be selected and optimal study designs can be implemented.
Fig. 1
a Patients with chronic hepatitis B are characterized by a high viral load and antigenaemia, as well as a small number of dysfunctional HBV-specific T-cells. b Failure of combining therapeutic vaccine and nucleos(t)ide analogue treatment could be attributed to T cell exhaustion induced by PD1 and PD-L1 engagement. c Combining anti-PD1, an immune checkpoint inhibitor, with strategy b may be a solution to cure chronic HBV infection
Perspectives |
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发表于 2017-4-21 18:26
