Designer T cells by T cell receptor replacement

Sommermeyer, Daniel; Neudorfer, Julia; Weinhold, Monika; Leisegang, Matthias; Engels, Boris; Noeßner, Elfriede; Heemskerk, Mirjam H.M.; Charo, Jehad; Schendel, Dolores J.; Blankenstein, Thomas; Bernhard, Helga; Uckert, Wolfgang

doi:10.1002/eji.200636539

Cited by 86 publications

(94 citation statements)

References 36 publications

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“…However, the transfer of TCR genes into terminally differentiated T cells also creates some drawbacks. Ideally, the introduction of a TCR harboring a new Ag specificity into an adult T cell should displace the endogenous TCR from the cell surface (12). When, however, the transferred TCR is not successful in doing so, stimulation of the T cell via its introduced, transgenic TCR can lead to activation of the previously tolerant T cell.…”

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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

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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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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

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“…The sequences of the peptides used in this study are as follows: MART-1 27L [26][27][28][29][30][31][32][33][34][35] (ELAGIGILTV), gp100 210M 209-217 (IMDQVPFSV), and p53 264-272 (LLGRNSFEV).…”

Section: Peptidementioning

confidence: 99%

“…Consequently, Jurkat RT3-T3.5 expressing different MART-1 TCR combinations (as indicted in Fig. 7B) were cocultured in the presence of MART-1 [26][27][28][29][30][31][32][33][34][35] peptide-pulsed T2 cells or mock pulsed as a control. We then stained them with a MART-1/HLA-A2 tetramer to assess the level of specific TCR surface expression and calculated the level of TCR internalization relative to unstimulated lymphocytes.…”

Section: Minimally Murinized Enhanced Tcr Function Is Associated Withmentioning

confidence: 99%

“…Preferential pairing of the exogenous TCR chains can be achieved by molecularly altering the primary structure of both the C regions of the a and b TCR chains to different extent: by inverting residues in the CaCb interface (knob into holes) (19), by fusing CD3-z domains to the C terminus of the TCR chains (20), or as we and others recently demonstrated, by introducing a second interchain disulfide bond (21,22). Recently, we also described an additional strategy based on the swapping of the human C regions with murine ones or "murinization" (23), because it was observed that murine TCRs are better expressed than (and can replace) human TCRs more efficiently on the surface of human lymphocytes (24)(25)(26). This also translated in improved cytokine release and cytotoxicity mediated by murinized TCRs (8,15,23,27) and was associated with an improved pairing of the TCR chains as well as a stronger interaction with the CD3 complex (23).…”

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confidence: 99%

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Selected Murine Residues Endow Human TCR with Enhanced Tumor Recognition

Bialer

Horovitz-Fried

Ya’acobi

et al. 2010

The Journal of Immunology

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“…TCR-engineered T cells express an endogenous TCR that may lead to poor expression of the therapeutic TCR because of either competition between the two TCR for components of the CD3 complex or due to mixed TCR composed of the a-chain of one TCR and the b-chain of the other [51,57]. Considering the high frequency of HLA-alloreactive T cells in the unselected repertoire, the mixed TCR may be alloreactive and cause GVH disease [51].…”

Section: Att -Circumventing Tolerance To Tumorsmentioning

confidence: 99%

Making and circumventing tolerance to cancer

Kammertoens¹,

Blankenstein²

2009

Eur J Immunol

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The interactions between cancer and immune cells are complex. Even though the mutations that cause cancer can create new antigens that are potentially ''visible'' to T cells, in most experimental model systems the growth of tumors is accompanied by induction of T-cell tolerance towards the tumor. How tolerance to tumors is induced and how tolerance can be broken by immunotherapy have been a main focus in cancer immunology. Here, we discuss experimental models used in cancer immunology. We argue that, while it is obviously easy for tumors to induce tolerance, it should be as easy to circumvent tolerance by the adoptive transfer of tumor-antigen-reactive T cells. Effective adoptive T-cell therapy has become feasible by methods to identify TCR against tumor-associated (self-) antigens with high affinity and to graft a new antigen specificity to patients' T cells by TCR gene transfer.Key words: Adoptive T-cell therapy . Experimental cancer models . Tolerance .Tumor immunity IntroductionThe choice of experimental systems that adequately reflect cancer development in humans is essential to better understand the complex interactions between tumors and the immune system. Historically, transplantable tumor models or tumors induced by oncogenic viruses were investigated [1]. Additionally, chemical carcinogenesis and skin tumor induction by UV-light were used to analyze immune responses to tumors [2,3]. Cancer-prone mice expressing an oncogene in a tissue-specific fashion have been used to employ immunotherapeutic strategies [4]. The Cre-LoxP recombination system and drug-inducible oncogene induction represent more recent technologies allowing spatio-temporal tumor induction that better mimic cancer development in humans [5]. Additionally, gene-deficient mice with various immune deficiencies and mice with transgenic T-cell receptors specific for tumor antigens were used to analyze the role of the immune system for tumor development. Data from all these experimental cancer models have contributed to our current understanding of tumor-immune system interactions. Importantly, recent developments have demonstrated the power of adoptively transferred T cells to reject large tumors. Here, we give a short overview of experimental cancer models, the discoveries they have brought about and the limitations they have. Finally, we argue that adoptive T-cell therapy (ATT) not only holds the greatest promise to break (or more precisely to circumvent) tolerance against established tumors but also that it is a feasible approach in the clinic, if combined with genetic engineering of antigen-specific T cells. Experimental cancer modelsTransplantable tumor modelsThe observation that tumors can be transplanted from one animal to another dates back more than a century [6]. Initial studies were difficult, because mice were not inbred and transplantation On the other hand, many important discoveries have been made in tumor transplantation models. For example, the necessity of tumors to induce angiogenesis [12], the role of the tumor stroma for t...

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Designer T cells by T cell receptor replacement

Cited by 86 publications

References 36 publications

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

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

Selected Murine Residues Endow Human TCR with Enhanced Tumor Recognition

Making and circumventing tolerance to cancer

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