抗-PD-L1治疗在土拨鼠HBV感染模型中的安全性和有效性

StephenW

PLoS One. 2018 Feb 14;13(2):e0190058. doi: 10.1371/journal.pone.0190058. eCollection  2018.
Safety and efficacy of anti-PD-L1 therapy in the woodchuck model of HBV infection.Balsitis S1, Gali V1, Mason PJ1, Chaniewski S1, Levine SM1, Wichroski MJ1, Feulner M1, Song Y2, Granaldi K2, Loy JK3, Thompson CM4, Lesniak JA4, Brockus C5, Kishnani N6, Menne S7, Cockett MI1, Iyer R8, Mason SW1, Tenney DJ1.
Author information
1Virology Discovery, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.2Discovery Toxicology, Bristol-Myers Squibb, Princeton, New Jersey, United States of America.3Discovery Toxicology, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.4Immunotoxicology, Drug Safety Evaluation, Bristol-Myers Squibb, New Brunswick, New Jersey, United States of America.5Bioanalytical Sciences, Bristol-Myers Squibb, Princeton, New Jersey, United States of America.6Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey, United States of America.7Department of Microbiology and Immunology, Georgetown Univ. Medical Center, Washington, DC, United States of America.8Liver and Pancreas Tumor Center, Roswell Park Cancer Institute, Buffalo, New York, United States of America.

AbstractImmune clearance of Hepatitis B virus (HBV) is characterized by broad and robust antiviral T cell responses, while virus-specific T cells in chronic hepatitis B (CHB) are rare and exhibit immune exhaustion that includes programmed-death-1 (PD-1) expression on virus-specific T cells. Thus, an immunotherapy able to expand and activate virus-specific T cells may have therapeutic benefit for CHB patients. Like HBV-infected patients, woodchucks infected with woodchuck hepatitis virus (WHV) can have increased hepatic expression of PD-1-ligand-1 (PD-L1), increased PD-1 on CD8+ T cells, and a limited number of virus-specific T cells with substantial individual variation in these parameters. We used woodchucks infected with WHV to assess the safety and efficacy of anti-PD-L1 monoclonal antibody therapy (αPD-L1) in a variety of WHV infection states. Experimentally-infected animals lacked PD-1 or PD-L1 upregulation compared to uninfected controls, and accordingly, αPD-L1 treatment in lab-infected animals had limited antiviral effects. In contrast, animals with naturally acquired WHV infections displayed elevated PD-1 and PD-L1. In these same animals, combination therapy with αPD-L1 and entecavir (ETV) improved control of viremia and antigenemia compared to ETV treatment alone, but with efficacy restricted to a minority of animals. Pre-treatment WHV surface antigen (sAg) level was identified as a statistically significant predictor of treatment response, while PD-1 expression on peripheral CD8+ T cells, T cell production of interferon gamma (IFN-γ) upon in vitro antigen stimulation (WHV ELISPOT), and circulating levels of liver enzymes were not. To further assess the safety of this strategy, αPD-L1 was tested in acute WHV infection to model the risk of liver damage when the extent of hepatic infection and antiviral immune responses were expected to be the greatest. No significant increase in serum markers of hepatic injury was observed over those in infected, untreated control animals. These data support a positive benefit/risk assessment for blockade of the PD-1D-L1 pathway in CHB patients and may help to identify patient groups most likely to benefit from treatment. Furthermore, the efficacy of αPD-L1 in only a minority of animals, as observed here, suggests that additional agents may be needed to achieve a more robust and consistent response leading to full sAg loss and durable responses through anti-sAg antibody seroconversion.


PMID:29444087DOI:10.1371/journal.pone.0190058

StephenW

PLoS One。 2018年2月14日; 13（2）：e0190058。 doi：10.1371 / journal.pone.0190058。 eCollection 2018年。
抗-PD-L1治疗在土拨鼠HBV感染模型中的安全性和有效性。
Balsitis S1 Gali V1 Mason PJ1 Chaniewski S1 Levine SM1 Wichroski MJ1 Feulner M1 Song Y2 Granaldi K2 Loy JK3 Thompson CM4 Lesniak JA4 Brockus C5 Kishnani N6 Menne S7 Cockett MI1 Iyer R8 ，梅森SW1，坦尼DJ1。
作者信息

1
    Virology Discovery，Bristol-Myers Squibb，沃灵福德，康涅狄格州，美利坚合众国。
2
    Discovery Toxicology，Bristol-Myers Squibb，美国新泽西州普林斯顿。
3
    Discovery Toxicology，Bristol-Myers Squibb，沃灵福德，康涅狄格州，美利坚合众国。
4
    Immunotoxicology，Drug Safety Evaluation，Bristol-Myers Squibb，New Brunswick，New Jersey，United States of America。
五
    Bioanalytical Sciences，Bristol-Myers Squibb，美国新泽西州普林斯顿。
6
    Pharmaceutical Candidate Optimization，Bristol-Myers Squibb，美国新泽西州普林斯顿。
7
    乔治敦大学微生物与免疫学系医疗中心，美利坚合众国华盛顿特区。
8
    肝脏和胰腺肿瘤中心，罗斯韦尔公园癌症研究所，布法罗，纽约州，美利坚合众国。

抽象

乙型肝炎病毒（HBV）的免疫清除的特征在于广泛和强大的抗病毒T细胞应答，而慢性乙型肝炎（CHB）中的病毒特异性T细胞是罕见的并表现出免疫耗尽，包括程序性死亡-1（PD-1 ）在病毒特异性T细胞上的表达。因此，能够扩增和激活病毒特异性T细胞的免疫疗法对CHB患者可能具有治疗益处。与感染HBV的患者一样，土拨鼠肝炎病毒（WHV）感染的土拨鼠可以具有增加的PD-1-配体-1（PD-L1）的肝脏表达，增加CD8 + T细胞上的PD-1，以及有限数量的病毒 - 特异性T细胞在这些参数中具有显着的个体差异。我们使用WHV感染的土拨鼠评估抗-PD-L1单克隆抗体疗法（αPD-L1）在多种WHV感染状态下的安全性和功效。与未感染的对照相比，实验感染的动物缺乏PD-1或PD-L1上调，因此实验室感染动物中的αPD-L1处理具有有限的抗病毒作用。相反，具有天然获得性WHV感染的动物显示升高的PD-1和PD-L1。在这些相同的动物中，与单独的ETV治疗相比，αPD-L1和恩替卡韦（ETV）的联合治疗改善了对病毒血症和抗原血症的控制，但是仅限于少数动物的功效。预处理WHV表面抗原（sAg）水平被确定为治疗应答的统计学显着预测因子，而外周CD8 + T细胞上的PD-1表达，体外抗原刺激（WHV）后干扰素γ（IFN-γ）的T细胞产生ELISPOT）和循环水平的肝酶不是。为了进一步评估此策略的安全性，在急性WHV感染中测试αPD-L1，以在肝脏感染程度和抗病毒免疫应答预期最大时模拟肝损伤的风险。未感染的，未处理的对照动物的血清标记物的肝损伤没有观察到显着增加。这些数据支持阻断CHB患者中PD-1：PD-L1途径的积极益处/风险评估，并有助于确定最可能从治疗中获益的患者群。此外，如本文所观察到的，αPD-L1在仅少数动物中的功效表明可能需要其他药剂以获得更强的和一致的响应，从而通过抗sAg抗体血清转化导致完全的sAg消失和持久的响应。

结论：
    29444087
DOI：
    10.1371 / journal.pone.0190058

StephenW

http://journals.plos.org/plosone ... ournal.pone.0190058