Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy

Bendle, Gavin; Linnemann, Carsten; Hooijkaas, Anna I.; Bies, Laura; Witte, Moniek A. de; Jorritsma, Annelies; Kaiser, Andrew; Pouw, Nadine; Debets, Reno; Kieback, Elisa; Uckert, Wolfgang; Song, Ji‐Ying; Haanen, John B.A.G.; Schumacher, Ton N.

doi:10.1038/nm.2128

Cited by 387 publications

(349 citation statements)

References 41 publications

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“…Experiments with a panel of TCRs with varied affinity and targeting self-antigens show that the induction of anti-tumor activity and autoimmunity are closely coupled 93 . Furthermore, autoimmune syndromes might occur following the adoptive transfer of transgenic T cells that retain the endogenous TCR 94 , presumably owing to the formation of heterodimers that create self-reactive specificities.…”

Section: Box 1 Adoptive T Cell Therapymentioning

confidence: 99%

Is autoimmunity the Achilles' heel of cancer immunotherapy?

June

Warshauer

Bluestone

2017

Nat Med

388

308

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Section: Box 1 Adoptive T Cell Therapymentioning

confidence: 99%

Is autoimmunity the Achilles' heel of cancer immunotherapy?

June

Warshauer

Bluestone

2017

Nat Med

388

308

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“…The ideal effector T cell for adoptive therapy should be 1) available in sufficient numbers, 2) specific for the targeted Ag, and 3) possess long-lasting in vivo persistence as a prerequisite for successful therapy (7).…”

mentioning

confidence: 99%

Immunotherapy with TCR-Redirected T Cells: Comparison of TCR-Transduced and TCR-Engineered Hematopoietic Stem Cell–Derived T Cells

Stärck

Popp

Pircher

et al. 2014

The Journal of Immunology

Self Cite

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Redirecting Ag specificity by transfer of TCR genes into PBLs is an attractive method to generate large numbers of cytotoxic T cells for immunotherapy of cancer and viral diseases. However, transferred TCR chains can pair with endogenous TCR chains, resulting in the formation of mispaired TCR dimers and decreased or unspecific reactivity. TCR gene transfer into hematopoietic stem cells (HSCs) is an alternative to create T cells with desired Ag specificity, because in this case expression of endogenous TCR chains is then less likely owing to allelic exclusion. We generated TCR-transduced T cells from peripheral T cells using the lymphocytic choriomeningitis virus–specific P14 TCR. After transfer of the P14 TCR genes into HSCs and subsequent reconstitution of irradiated mice, TCR-engineered HSC-derived T cells were produced. We then compared the Ag-specific T cell populations with P14 TCR-transgenic T cells for their therapeutic efficiency in three in vivo models. In this study, we demonstrate that TCR-transduced T cells and TCR-engineered HSC-derived T cells are comparable in controlling lymphocytic choriomeningitis virus infection in mice and suppress growth of B16 tumor cells expressing the cognate Ag in a comparable manner.

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“…Second, the transduced TCR α and β chains can mispair with endogenous TCRs 9 , which may reduce expression level of the TCR of interest. In addition, the mispaired TCRs may cause autoimmunity in vivo 11 . Finally, there is only a limited time frame the transduced T-cells can be used.…”

Section: Discussionmentioning

confidence: 99%

Retroviral Transduction of T-cell Receptors in Mouse T-cells

Shi

Malecek

Pérez-García

et al. 2010

JoVE

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T-cell receptors (TCRs) play a central role in the immune system. TCRs on T-cell surfaces can specifically recognize peptide antigens presented by antigen presenting cells (APCs) 1. This recognition leads to the activation of T-cells and a series of functional outcomes (e.g. cytokine production, killing of the target cells). Understanding the functional role of TCRs is critical to harness the power of the immune system to treat a variety of immunology related diseases (e.g. cancer or autoimmunity).It is convenient to study TCRs in mouse models, which can be accomplished in several ways. Making TCR transgenic mouse models is costly and time-consuming and currently there are only a limited number of them available [2][3][4] . Alternatively, mice with antigen-specific T-cells can be generated by bone marrow chimera. This method also takes several weeks and requires expertise 5 . Retroviral transduction of TCRs into in vitro activated mouse T-cells is a quick and relatively easy method to obtain T-cells of desired peptide-MHC specificity. Antigen-specific T-cells can be generated in one week and used in any downstream applications. Studying transduced T-cells also has direct application to human immunotherapy, as adoptive transfer of human T-cells transduced with antigen-specific TCRs is an emerging strategy for cancer treatment 6 .

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Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy

Cited by 387 publications

References 41 publications

Is autoimmunity the Achilles' heel of cancer immunotherapy?

Is autoimmunity the Achilles' heel of cancer immunotherapy?

Immunotherapy with TCR-Redirected T Cells: Comparison of TCR-Transduced and TCR-Engineered Hematopoietic Stem Cell–Derived T Cells

Retroviral Transduction of T-cell Receptors in Mouse T-cells

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