Prospects and Limitations of T Cell Receptor Gene Therapy

Coccoris, Miriam; Witte, Moniek de; Schumacher, Ton N.

doi:10.2174/156652305774964730

Cited by 25 publications

(21 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The infusion of antigenspecific T cell populations is considered valuable to restore antiviral immunity in transplant recipients and other immunocompromised patients (29), and a study in which the feasibility of infusion of CMV-specific T cells obtained by MHC-tetramerassisted enrichment has been reported (30). In addition, selection of defined T cells may be used to enhance the antitumor effect of allogeneic hematopoietic stem cell transplantation (31) and TCR gene therapy protocols (27,32,33).…”

Section: Discussionmentioning

confidence: 99%

Conditional MHC class I ligands and peptide exchange technology for the human MHC gene products HLA-A1, -A3, -A11, and -B7

Bakker¹,

Hoppes

Linnemann³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

141

167

View full text Add to dashboard Cite

Major histocompatibility complex (MHC) class I multimer technology has become an indispensable immunological assay system to dissect antigen-specific cytotoxic CD8 ؉ T cell responses by flow cytometry. However, the development of high-throughput assay systems, in which T cell responses against a multitude of epitopes are analyzed, has been precluded by the fact that for each T cell epitope, a separate in vitro MHC refolding reaction is required. We have recently demonstrated that conditional ligands that disintegrate upon exposure to long-wavelength UV light can be designed for the human MHC molecule HLA-A2. To determine whether this peptide-exchange technology can be developed into a generally applicable approach for high throughput MHC based applications we set out to design conditional ligands for the human MHC gene products HLA-A1, -A3, -A11, and -B7. Here, we describe the development and characterization of conditional ligands for this set of human MHC molecules and apply the peptide-exchange technology to identify melanoma-associated peptides that bind to HLA-A3 with high affinity. The conditional ligand technology developed here will allow high-throughput MHC-based analysis of cytotoxic T cell immunity in the vast majority of Western European individuals.M HC Class I molecules are heterotrimeric complexes consisting of an invariant light chain called ␤2-microglobulin (␤2m), a polymorphic heavy chain (HC) and an Ϸ8-to 11-aa peptide ligand. These peptide-MHC (pMHC) complexes are recognized by the T cell receptor (TCR) of CD8 ϩ T cells in a peptide-specific fashion, and this interaction forms the molecular basis of antigen recognition by CD8 ϩ T cells. In the past decade, the mapping of pathogen-specific and autoimmune-or cancer-associated T cell epitopes has been a major driving force in the development of assay systems for immunomonitoring. In addition, knowledge of such T cell epitopes forms a cornerstone in the development of vaccine-based or adoptive T cell therapies. As a first step in the mapping of disease-associated T cell epitopes, peptide fragments of disease-associated proteomes may be analyzed for binding to MHC molecules of interest, and subsequent assays can then be used to determine whether T cell reactivity against such pMHC complexes does occur. As demonstrated in a landmark study by Altman and colleagues (1), such antigen-specific T cell reactivity can efficiently be detected by the staining of T cell populations with recombinant fluorescent multimeric MHC molecules.There is an increasing interest in the development of assay systems, such as MHC-based microarrays, that can monitor a multitude of T cell responses in parallel (2-4). Unfortunately, current technology does not allow for the high-throughput generation of different pMHC complexes, thereby limiting the utility of these techniques. Specifically, because MHC class I complexes that are devoid of peptide are markedly unstable (5, 6), current production processes for recombinant MHC complexes require inclusion of a specific T cell epi...

show abstract

Section: Discussionmentioning

confidence: 99%

Conditional MHC class I ligands and peptide exchange technology for the human MHC gene products HLA-A1, -A3, -A11, and -B7

Bakker¹,

Hoppes

Linnemann³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

141

167

View full text Add to dashboard Cite

show abstract

“…Although this type of "off-target" autoimmunity has not been seen in mouse studies (4) or in a first clinical trial in melanoma patients (5), this clearly does not exclude the possibility that such side effects will occur when other TCRs are used, or when conditioning regimens or adjuvant treatments are modified. In addition to these off-target effects, the potential occurrence of on-target autoimmunity by CR-or TCR-modified T cells may be a reason for concern, in particular for target Ags that are also expressed in vital tissues (28,29). Safety switch systems such as HSV-TK, CD20, Myc-tagged transgenes, and iCasp9 M (9,13,16,30) that can be used for the conditional elimination of infused T lymphocytes in either of the above clinical settings should meet three conditions.…”

Section: Discussionmentioning

confidence: 99%

An Inducible Caspase 9 Safety Switch Can Halt Cell Therapy-Induced Autoimmune Disease

Witte

Jorritsma²,

Swart³

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

Transfer of either allogeneic or genetically modified T cells as a therapy for malignancies can be accompanied by T cell-mediated tissue destruction. The introduction of an efficient “safety switch” can potentially be used to control the survival of adoptively transferred cell populations and as such reduce the risk of severe graft-vs-host disease. In this study, we have tested the value of an inducible caspase 9-based safety switch to halt an ongoing immune attack in a murine model for cell therapy-induced type I diabetes. The data obtained in this model indicate that self-reactive T cells expressing this conditional safety switch show unimpaired lymphopenia- and vaccine-induced proliferation and effector function in vivo, but can be specifically and rapidly eliminated upon triggering. These data provide strong support for the evaluation of this conditional safety switch in clinical trials of adoptive cell therapy.

show abstract

“…More importantly, for essentially all other human cancers, the routine generation of highly tumor-reactive TIL cultures has not been successful. With the aim to develop protocols for adoptive therapy that do not rely on the availability of TIL, it has been proposed to provide autologous T cells with tumor cell-specificity, by genetic introduction of a tumor-specific TCR (4,5). The in vivo function of TCR modified T cells has been studied extensively in mouse models.…”

Section: Long-term Functionality Of Tcr-transduced T Cells In Vivomentioning

confidence: 99%

Long-Term Functionality of TCR-Transduced T Cells In Vivo

Coccoris¹,

Swart²,

Witte³

et al. 2008

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

To broaden the applicability of adoptive T cell therapy to cancer types for which tumor-specific T cells cannot routinely be isolated, an effort has been made to develop the transfer of tumor-specific TCR genes into autologous T cells as a novel immunotherapeutic approach. Although such TCR-modified T cells have been shown to react to Ag encounter and can be used to break tolerance to defined self-Ags, the persistence and capacity for renewed expansion of TCR-modified T cells has not been analyzed. To establish whether TCR-transduced T cells can provide recipients with long-term Ag-specific immune protection, we analyzed long-term function of TCR transduced T cells in mouse model systems. We demonstrate that polyclonal populations of T cells transduced with a class I restricted OVA-specific TCR are able to persist in vivo and respond upon re-encounter of cognate Ag as assessed by both proliferation and cytolytic capacity. These experiments indicate that TCR gene transfer can be used to generate long-term Ag-specific T cell responses and provide a useful model system to assess the factors that can promote high-level persistence of TCR-modified T cells.

show abstract

Prospects and Limitations of T Cell Receptor Gene Therapy

Cited by 25 publications

References 60 publications

Conditional MHC class I ligands and peptide exchange technology for the human MHC gene products HLA-A1, -A3, -A11, and -B7

Conditional MHC class I ligands and peptide exchange technology for the human MHC gene products HLA-A1, -A3, -A11, and -B7

An Inducible Caspase 9 Safety Switch Can Halt Cell Therapy-Induced Autoimmune Disease

Long-Term Functionality of TCR-Transduced T Cells In Vivo

Contact Info

Product

Resources

About