Challenges of CAR- and TCR-T cell–based therapy for chronic infections

Bertoletti, Antonio; Tan, Anthony T.

doi:10.1084/jem.20191663

Cited by 34 publications

(34 citation statements)

References 15 publications

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“…In vitro transcribed TCR mRNA redirected T cells express the transferred TCR genes for several days. Although they display less cytotoxic potential when compared to virally transduced T cells in vitro, [64][65][66], they have proven to be safe and effective in a clinical trial involving a chronic HBV patient with extensive HCC metastasis [58]. Administering multiple escalating infusions of mRNA TCR-redirected T cells specific for HBV antigens resulted in reduction of the metastases, which could not be explained entirely by the direct lytic effect of the administered T cells, but rather by their induction of a secondary antitumor response.…”

Section: Gene Transfer Methodsmentioning

confidence: 99%

“…In this study, the TCR paired sequences were identified from cells that were also expressing high levels of IFN-γ and IL-2 after co-culture with tandem minigene-transfected or peptide-pulsed autologous patient APCs. The major limitation of this method is the cell number required to perform the assay, which can be an issue when screening T cell populations where the reactive clonotypes are present at low frequency as in chronic viral hepatitis and cancer [64].…”

Section: Single Cell Sequencingmentioning

confidence: 99%

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Chronic Viral Liver Diseases: Approaching the Liver Using T Cell Receptor-Mediated Gene Technologies

Healy

Pasetto

Sobkowiak

et al. 2020

Cells

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Chronic infection with viral hepatitis is a major risk factor for liver injury and hepatocellular carcinoma (HCC). One major contributing factor to the chronicity is the dysfunction of virus-specific T cell immunity. T cells engineered to express virus-specific T cell receptors (TCRs) may be a therapeutic option to improve host antiviral responses and have demonstrated clinical success against virus-associated tumours. This review aims to give an overview of TCRs identified from viral hepatitis research and discuss how translational lessons learned from cancer immunotherapy can be applied to the field. TCR isolation pipelines, liver homing signals, cell type options, as well as safety considerations will be discussed herein.

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Section: Gene Transfer Methodsmentioning

confidence: 99%

Section: Single Cell Sequencingmentioning

confidence: 99%

Chronic Viral Liver Diseases: Approaching the Liver Using T Cell Receptor-Mediated Gene Technologies

Healy

Pasetto

Sobkowiak

et al. 2020

Cells

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“…To overcome this problem, engineering of CAR-T cells could be done through mRNA electroporation, rather than using viral transduction, to obtain virus-specific T cells that will survive only for a limited time ( Figure 3 ). The use of mRNA electroporation has been shown to result in only transient expression (3–5 days) of the CAR and thus is expected to decrease the risk for its off-target effects [ 81 ]. This technological adaptation can also reduce the viral contamination that can come from the viral transduction method of conventional CAR-T cell engineering.…”

Section: Chimeric Antigen Receptor T-cell (Car-t) Therapymentioning

confidence: 99%

Emerging Prevention and Treatment Strategies to Control COVID-19

et al. 2020

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has now become a serious global threat after inflicting more than 8 million infections and 425,000 deaths in less than 6 months. Currently, no definitive treatment or prevention therapy exists for COVID-19. The unprecedented rise of this pandemic has rapidly fueled research efforts to discover and develop new vaccines and treatment strategies against this novel coronavirus. While hundreds of vaccines/therapeutics are still in the preclinical or early stage of clinical development, a few of them have shown promising results in controlling the infection. Here, in this review, we discuss the promising vaccines and treatment options for COVID-19, their challenges, and potential alternative strategies.

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“…A recent study demonstrated that the adoptive transfer of grafted T cells provides a promising novel therapeutic approach wherein the retroviral delivery of T cell chimeric antigen receptors (CARs) can enable primary human T cells to detect HBsAg-positive hepatocytes, release IFN-γ and IL-2, and lyse HBV replicating cells [ 148 ]. Another study found that T cells with a CAR specific for HBV envelope proteins could localize to the liver in mice, reducing HBV replication and only causing transient liver damage [ 149 ]; however, the adoption of this approach to treat infectious diseases has been met with considerable resistance [ 150 ].…”

Section: Adaptive Immune Response Modulationmentioning

confidence: 99%

Targeting Host Innate and Adaptive Immunity to Achieve the Functional Cure of Chronic Hepatitis B

et al. 2020

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Despite the availability of an effective preventive vaccine for hepatitis B virus (HBV) for over 38 years, chronic HBV (CHB) infection remains a global health burden with around 257 million patients. The ideal treatment goal for CHB infection would be to achieve complete cure; however, current therapies such as peg-interferon and nucleos(t)ide analogs are unable to achieve the functional cure, the newly set target for HBV chronic infection. Considering the fact functional cure has been accepted as an endpoint in the treatment of chronic hepatitis B by scientific committee, the development of alternative therapeutic strategies is urgently needed to functionally cure CHB infection. A promising target for future therapeutic strategies is immune modulation to restore dysfunctional HBV-specific immunity. In this review, we provide an overview of the progress in alternative therapeutic strategies, including immune-based therapeutic approaches that enhance host innate and adaptive immunity to achieve and increase the functional cure from CHB infection.

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Challenges of CAR- and TCR-T cell–based therapy for chronic infections

Abstract: While therapy with T cells engineered with a chimeric antigen receptor (CAR) or a classical T cell receptor (TCR) is revolutionizing cancer treatment, its adoption in infectious diseases has been met with considerable resistance. Can we find its value for the cure of infections?

Cited by 34 publications

References 15 publications

Chronic Viral Liver Diseases: Approaching the Liver Using T Cell Receptor-Mediated Gene Technologies

Chronic Viral Liver Diseases: Approaching the Liver Using T Cell Receptor-Mediated Gene Technologies

Emerging Prevention and Treatment Strategies to Control COVID-19

Targeting Host Innate and Adaptive Immunity to Achieve the Functional Cure of Chronic Hepatitis B

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