T Cells Expressing a Chimeric Antigen Receptor That Binds Hepatitis B Virus Envelope Proteins Control Virus Replication in Mice

Krebs, K.; Böttinger, N.; Huang, Li–Rung; Chmielewski, Markus; Arzberger, Silke; Gasteiger, Georg; Jäger, Clemens; Schmitt, Edgar; Bohne, Felix; Aichler, Michaela; Uckert, Wolfgang; Abken, Hinrich; Heikenwälder, Mathias; Knolle, Percy A.; Protzer, Ulrike

doi:10.1053/j.gastro.2013.04.047

Cited by 191 publications

(161 citation statements)

References 39 publications

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“…Ji et al reported that a fusion protein of T cell receptor-like antibodies (TCR-L)/IFN-a augmented an IFN-a response selectively against HBV-infected cells [48]. In mice, chimeric antigen receptors directed against HBV envelope proteins localized T cells in the liver, resulting in the reduction of HBV replication [49].…”

Section: Immunological Intervention Against Hbv Infectionmentioning

confidence: 99%

Host–virus interactions in hepatitis B and hepatitis C infection

Yoshio

Kanto

2016

J Gastroenterol

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Hepatitis B virus (HBV) and hepatitis C virus (HCV) are among the most endemic pathogens worldwide, with more than 500 million people globally currently infected with these viruses. These pathogens can cause acute and chronic hepatitis that progress to liver cirrhosis or hepatocellular carcinoma. Both viruses utilize multifaceted strategies to evade the host surveillance system and fall below the immunological radar. HBV has developed specific strategies to evade recognition by the innate immune system and is acknowledged to be a stealth virus. However, extensive research has revealed that HBV is recognized by dendritic cells (DCs) and natural killer (NK) cells. Indoleamine-2, 3-dioxygenase is an enforcer of sequential immune reactions in acute hepatitis B, and this molecule has been shown to be induced by the interaction of HBV-infected hepatocytes, DCs, and NK cells. The interleukin-28B genotype has been reported to influence HCV eradication either therapeutically or spontaneously, but the biological function of its gene product, a type-III interferon (IFN-k3), remains to be elucidated. Human BDCA3 ? DCs have also been shown to be a potent producer of IFN-k3 in HCV infection, suggesting the possibility that BDCA3 ? DCs could play a key role in developing therapeutic HCV vaccine. Here we review the current state of research on immune responses against HBV and HCV infection, with a specific focus on innate immunity. A comprehensive study based on clinical samples is urgently needed to improve our understanding of the immune mechanisms associated with viral control and thus to develop novel immune modulatory therapies to cure chronic HBV and HCV infection.

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Section: Immunological Intervention Against Hbv Infectionmentioning

confidence: 99%

Host–virus interactions in hepatitis B and hepatitis C infection

Yoshio

Kanto

2016

J Gastroenterol

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“…This strategy has also been proposed for the treatment of viral infection, including HIV-1, hepatitis B virus, and hepatitis C virus (24,25). Previous reports have described the generation of HIV-1-specific CAR-T cells by connection of an extracellular antigenbinding domain to intracellular T cell activation domains (e.g., CD3 and CD28).…”

mentioning

confidence: 99%

Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4 ⁺ T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy

Liu

Zou

et al. 2016

J Virol

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Despite the advent of combined antiretroviral therapy (cART), the persistence of viral reservoirs remains a major barrier to curing human immunodeficiency virus type 1 (HIV-1) infection. Recently, the shock and kill strategy, by which such reservoirs are eradicated following reactivation of latent HIV-1 by latency-reversing agents (LRAs), has been extensively practiced. It is important to reestablish virus-specific and reliable immune surveillance to eradicate the reactivated virus-harboring cells. In this report, we attempted to reach this goal by using newly developed chimeric antigen receptor (CAR)-T cell technology. To generate anti-HIV-1 CAR-T cells, we connected the single-chain variable fragment of the broadly neutralizing HIV-1-specific antibody VRC01 to a third-generation CAR moiety as the extracellular and intracellular domains and subsequently transduced this into primary CD8 ؉ T lymphocytes. We demonstrated that the resulting VC-CAR-T cells induced T cell-mediated cytolysis of cells expressing HIV-1 Env proteins and significantly inhibited HIV-1 rebound after removal of antiviral inhibitors in a viral infectivity model in cell culture that mimics the termination of the cART in the clinic. Importantly, the VC-CAR-T cells also effectively induced the cytolysis of LRA-reactivated HIV-1-infected CD4؉ T lymphocytes isolated from infected individuals receiving suppressive cART. Our data demonstrate that the special features of genetically engineered CAR-T cells make them a particularly suitable candidate for therapeutic application in efforts to reach a functional HIV cure. IMPORTANCEThe presence of latently infected cells remains a key obstacle to the development of a functional HIV-1 cure. Reactivation of dormant viruses is possible with latency-reversing agents, but the effectiveness of these compounds and the subsequent immune response require optimization if the eradication of HIV-1-infected cells is to be achieved. Here, we describe the use of a chimeric antigen receptor, comprised of T cell activation domains and a broadly neutralizing antibody, VRC01, targeting HIV-1 to treat the infected cells. T cells expressing this construct exerted specific cytotoxic activity against wild-type HIV-1-infected cells, resulting in a dramatic reduction in viral rebound in vitro, and showed persistent effectiveness against reactivated latently infected T lymphocytes from HIV-1 patients receiving combined antiretroviral therapy. The methods used in this study constitute an improvement over existing CD4-based CAR-T technology and offer a promising approach to HIV-1 immunotherapy. HIV-1 replication can be efficiently suppressed with combined antiretroviral therapy (cART). However, treatment must be maintained throughout the lifetime of the patient, as this virus can persist in a stable latent reservoir, constituting a major barrier to the establishment of an HIV-1 cure. To date, many strategies have been proposed for the eradication of HIV-1 reservoirs (1-3). Recent efforts have focused on the reactivation of ...

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“…5 Furthermore, these TCR-redirected T cells are not inhibited by the HBV antigen present in patients' sera, 5 a problem that might instead theoretically affect HBV-specific CAR-T cells. 6 The use of HBV antigen as a target for immunotherapy has however one important drawback: in patients with chronic HBV infection who developed HCC, HBV antigens are expressed not only by HCC cells with HBV-DNA integration but also by HBV infected hepatocytes. The risk of inducing a severe liver damage due to the targeting of normal infected hepatocytes cannot be ignored.…”

mentioning

confidence: 99%

T cell receptor-therapy in HBV-related hepatocellularcarcinoma

et al. 2015

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T Cells Expressing a Chimeric Antigen Receptor That Binds Hepatitis B Virus Envelope Proteins Control Virus Replication in Mice

Abstract: T cells with a CAR specific for HBV envelope proteins localize to the liver in mice to reduce HBV replication, causing only transient liver damage. This immune cell therapy might be developed for patients with chronic hepatitis B, regardless of their HLA type.

Cited by 191 publications

References 39 publications

Host–virus interactions in hepatitis B and hepatitis C infection

Host–virus interactions in hepatitis B and hepatitis C infection

Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4 ⁺ T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy

T cell receptor-therapy in HBV-related hepatocellularcarcinoma

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T Cells Expressing a Chimeric Antigen Receptor That Binds Hepatitis B Virus Envelope Proteins Control Virus Replication in Mice

Abstract: T cells with a CAR specific for HBV envelope proteins localize to the liver in mice to reduce HBV replication, causing only transient liver damage. This immune cell therapy might be developed for patients with chronic hepatitis B, regardless of their HLA type.

Cited by 191 publications

References 39 publications

Host–virus interactions in hepatitis B and hepatitis C infection

Host–virus interactions in hepatitis B and hepatitis C infection

Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4 + T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy

T cell receptor-therapy in HBV-related hepatocellularcarcinoma

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Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4 ⁺ T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy