Engineering immunosuppressive drug-resistant armored(IDRA)SARS-CoV-2 T cells for cell therapy

Solid organ transplant(SOT)recipients receive immunosuppressive drugs(ISDs)and are susceptible to developing severe COVID-19.Here,we analyze the Spike-specific T-cell response after 3 doses of mRNA vaccine in a group of SOT patients(n=136)treated with different ISDs.We demonstrate that a combination of a calcineurin inhibitor(CNI),mycophenolate mofetil(MMF),and prednisone(Pred)treatment regimen strongly suppressed the mRNA vaccine-induced Spike-specific cellular response.Such defects have clinical consequences because the magnitude of vaccine-induced Spike-specific T cells was directly proportional to the ability of SOT patients to rapidly clear SARS-CoV-2 after breakthrough infection.To then compensate for the T-cell defects induced by immunosuppressive treatment and to develop an alternative therapeutic strategy for SOT patients,we describe production of 6 distinct SARS-CoV-2 epitope-specific ISD-resistant T-cell receptor(TCR)-T cells engineered using the mRNA electroporation method with reactivity minimally affected by mutations occurring in Beta,Delta,Gamma,and Omicron variants.This strategy with transient expression characteristics marks an improvement in the immunotherapeutic field and provides an attractive and novel therapeutic possibility for immunosuppressed COVID-19 patients.

The immune tolerant phase of chronic HBV infection： new perspectives on an old concept

Chronic hepatitis B virus （HBV） infection progresses through distinct disease phases that are strongly associated with patient age. The so-called immune tolerant （IT） phase represents the classical early phase of infection; it is associated with high levels of HBV replication and lack of clinical signs of liver Inflammation. Whether this phase of HBV infection is also associated with immunological features of ＂tolerance＇ has recently been challenged. Here, we review the data that dispute this concept of immune tolerance and then propose an alternative interpretation of the immunopathological events that take place during this early phase of CHB infection.

Hepatitis B-specific T helper cell responses in uninfected infants born to HBsAg^(+)/HBeAg^(-) mothers

Vertically transmitted hepatitis B virus(HBV)usually causes chronic infection.While combined active–passive immunoprophylaxis in neonates of hepatitis B surface antigen-positive(HBsAg1)mothers at birth prevents vertical transmission,it is not yet clear whether neonates encounter the virus or its products in the absence of hepatitis B e antigen(HBeAg).This study was undertaken to investigate HBV antigen-specific T-cell responses in vaccinated neonates of HBsAg1/HBeAg2 mothers.Blood was collected from 46 HBsAg1 mothers and their neonates(subjects)as well as 24 age-matched controls.All neonates of HBsAg1 mothers received appropriate immunoprophylaxis,and HBsAg and hepatitis B surface antibody(anti-HBs)antibody titers were determined after completion of the vaccination course.Peripheral blood mononuclear cells(PBMCs)from infants at birth,1 and 6 months of age were stimulated with recombinant HBsAg,hepatitis B core antigen(HBcAg)and mitogen,and interferon(IFN)-c concentrations were determined by ELISA.HBsAg-induced production of IL-2,IL-5,IL-6 and IL-10 was assessed using a cytometric bead array kit on cells from 6-month-old neonates post-vaccination.All neonates were HBsAg2 and responded to vaccination.Increased IFN-c production following HBcAg stimulation was seen in 30.4%of neonates born to HBsAg1/HBeAg2 mothers.Subjects demonstrated significantly higher IL-2 production post-HBsAg stimulation,whereas IL-5,IL-6 and IL-10 cytokine responses were not significantly different.Almost one-third of uninfected neonates developed viral antigen-induced IFN-c production,suggesting that they had been exposed to virions or viral derivatives.This encounter,however,did not impair their T-cell responses to vaccination.

SARS-CoV-2-specific T cells in infection and vaccination

During viral infections,antibodies and T cells act together to prevent pathogen spread and remove virus-infected cells.Virusspecific adaptive immunity can,however,also trigger pathological processes characterized by localized or systemic inflammatory events.The protective and/or pathological role of virus-specific T cells in SARS-CoV-2 infection has been the focus of many studies in COVID-19 patients and in vaccinated individuals.Here,we review the works that have elucidated the function of SARS-CoV-2-specific T cells in patients and in vaccinated individuals.Understanding whether SARS-CoV-2-specific T cells are more linked to protection or pathogenesis is pivotal to define future therapeutic and prophylactic strategies to manage the current pandemic.

T cell immunotherapy in hepatitis B Virus related hepatocellular carcinoma

Chronic hepatitis B Virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). While multiple treatment modalities are available, liver transplantation remains the sole curative treatment for advanced stages of HCC, and hence new treatment approaches are required to fulfill this unmet need of curative HCC therapy. Our first-in-man proof-of-concept adoptive T-cell immunotherapy against HBV related hepatocellular carcinoma metastases has shown promising results. Here, we review the development of T-cell immunotherapy targeting HBV antigens for the treatment of HBV-HCC and discuss the practical considerations for the safe and effective use in clinics.

Overview of the special issue on HBV immunity

Hepatitis B virus （HBV） has a unique rela- tionship with humans. It is not only very suc- cessful in spreading amongst our species （a third of the human population has been in contact with the virus and approximately 200-300 million people are actively infected）, but it has adapted to and co-evolved with us. This long-term relationship is demonstrated by the recent detection of hepadnavirus gen- omes in Mesozoic birds2 and by the estima- tion that HBV was already present in early humans at least 40, 000 years ago.3

Protection from infection or disease? Re-evaluating the broad immunogenicity of inactivated SARS-CoV-2 vaccines

How do we measure vaccine efficacy? The strictest but also easiest parameter to determine vaccine efficacy is its ability to block infection.Indeed, if a vaccine is able to block infection, this necessarily follows that it will also prevent both disease development and viral transmission. As a consequence, antibodies, specifically neutralising antibodies, have been used as the “gold standard” correlate of protection to measure SARS-CoV-2 vaccine efficacy, given their ability to block infection.

Personalized T-cell therapy in liver transplanted patients with hepatitis B virus related hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a deadly malignancy which typically occurs in the context of chronic liver inflammation.Chronic hepatitis B virus(HBV)infection is considered a major global cause of HCC development.At the moment,liver transplantation is the only curative modality for HBV-associated HCC.However,some patients develop HBV-HCC recurrence after liver transplantation,leaving them with very limited therapeutic options.Adoptive cell therapy with HBV-specific T cell receptor(TCR)that redirects T cells against HCC relapses has shown promising results in such HBV-HCC patients.In this mini-review,we discuss the application of this personalized T cell therapy,and highlight mRNA electroporation as an efficient tool for engineering safe and efficient TCR-redirected T cells for the treatment of liver transplant patients with HBV-HCC metastasis.