The 2018 Medicine Nobel Prize was awarded jointly to two immunologists, James P. Allison at the University of Texas MD Anderson Cancer Center in Houston and Tasuku Honjo at Kyoto University in Japan, who pioneered a new way to treat cancers (Ledford et al. 2018). Both Laureates have shown how so called "immune checkpoints" on T cells can be used to manipulate the immune responses so that T cells can efficiently attack cancer cells. Using the immune system to fight cancers has been investigated for more than a 100 years. Recent advances in cancer immunotherapy, particularly immune checkpoint blockade therapy have dramatically changed the therapeutic strategy against advanced cancers. Through inhibiting negative immune regulation, these approaches have demonstrated improved overall survival for patients with advanced cancers. Importantly, for some of the patients treated with such strategies, their tumors seem to totally disappear.
In addition to immunosurveillance of cancer, a prime function of immune system is the defense against infectious agents, such as viruses, bacteria, and fungi, et al. Similar to that in cancer, T cells are exposed to persistent antigen and become exhausted in many chronic viral infections, such as human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection. A cardinal feature of these exhausted T cells is over-expression of immune checkpoint molecules, such as CTLA4 and PD-1/PD-L1 (Wykes and Lewin 2018). Currently, control of both HIV and HBV requires life-long treatment, therefore, new strategies for treatment or cure for these viral infections are still urgently needed. The success of immune checkpoint therapy in cancer suggests that targeting these pathways could also be effective for treating chronic virus infection. As early as in 2006, Rafi and his colleagues reported that in vivo administration of PD-L1 blocking antibodies in mice chronically infected with lymphocytic choriomeningitis virus (LCMV) could rescue the antiviral function of exhausted CD8+ T cells to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load (Barber et al. 2006). In vivo administration of PD-1/PD-L1 blocking antibodies restores T cell function and reduces viral loads in animal models of chronical retrovirus infection, such as simian immunodeficiency virus (SIV)-infected rhesus macaques (Velu et al. 2009) and Friend virus (FV)-infected mice (Dietze et al. 2013; Akhmetzyanova et al. 2015). Meanwhile, multiple ex vivo studies using PBMCs collected from chronic hepatitis B patients have demonstrated that PD-1/PD-L1 blockade could lead to enhanced HBV-specific CD8+ T cell response (Boni et al. 2007; Fisicaro et al. 2010; Zhang et al. 2011). In 2014, we for the first time reported the effects of in vivo administration of PD-L1 blocking antibodies on enhancing virus-specific CD8+ T cell immunity in chronic woodchuck hepatitis virus (WHV) infected woodchucks, a classic animal model for HBV infection research (Liu et al. 2014). In the study, we demonstrated that anti-PD-L1 blockade mono-therapy could not rescue WHV-specific T cell function, however, anti-PD-L1 blockade in combination with antiviral treatment and therapeutic vaccination, potently enhanced WHV-specific CD8+ T cell immunity. The triple-therapy strategy led to sustained immunological control of viral infection after antivirals withdrawal, WHsAg seroconversion and even complete viral clearance in some treated animals (Liu et al. 2014). Very recently, two studies reported in parallel that HBsAg-specific and global B cells also showed increased expression of PD-1 during chronic HBV infection, and in vitro anti-PD-1 blockade could partially restore the functional maturation of HBsAgspecific B cells (Burton et al. 2018; Salimzadeh et al. 2018). These studies suggested that PD-1/PD-L1 blockade therapy in chronic hepatitis B (CHB) patients might be able to improve both HBV-specific T and B cell functionality.
Despite the inspiring results observed in preclinical studies (summarized in Table 1), limited progress has so far been made in clinical trials using immune checkpoint therapy for treating chronic viral infection diseases (summarized in Table 2). Due to the obvious safety concerns, many clinical trials of immune checkpoint blockade in individuals with chronic viral infection are designed and performed in the setting of cancer presence. Recently, an open label phase Ⅰ study of Nivolumab (anti-PD-1) with and without a hepatitis B vaccine GS-4774 in HBeAg negative chronic hepatitis B patients showed that Nivolumab was safe and well tolerated, and one treated patient underwent HBsAg seroconversion (Gane et al. 2017). A phase Ⅱ study of anti-PD-L1 therapy (BMS-936559, by Bristol-Myers Squibb) in HIV-infected patients showed a clear increase in Gag-specific CD4+ and CD8+ T cells in two out of the six treated patients. This is the only trial of an immune checkpoint therapy in HIV patients without malignancy. However, the study was recently ceased due to retinal toxicity observed in a simultaneous macaque study (Gay et al. 2017). Recently, a database analysis presented at the European Society for Medical Oncology 2018 Congress reported the feasibility of using immune checkpoint therapy to treat HIV patients who develop cancer. In total there were 20 HIV-positive cancer patients received Nivolumab treatment, and none experienced immunerelated adverse events. 24% of the 17 evaluable patients achieved a partial response to Nivolumab, which suggests that the overall response rate of HIV-positive patients seems to be similar to that of other cancer patients.
Table 1. Summary of preclinical studies in infectious diseases reporting benefits of targeting immune checkpoint.
Table 2. Summary of clinical trials targeting immune checkpoint in infectious diseases.