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Engineering T cells for cancer therapy.

Mansoor W, Gilham DE, Thistlethwaite FC, Hawkins RE - Br. J. Cancer (2005)

Bottom Line: These studies and others demonstrate the potential of T cells for the adoptive therapy of cancer.However, the significant technical issues relating to the production of natural tumour-specific T cells suggest that the application of this approach is likely to be limited at the moment.With the advent of retroviral gene transfer technology, it has become possible to efficiently endow T cells with antigen-specific receptors.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK, Department of Medical Oncology, University of Manchester, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Withington, Manchester, UK.

ABSTRACT
It is generally accepted that the immune system plays an important role in controlling tumour development. However, the interplay between tumour and immune system is complex, as demonstrated by the fact that tumours can successfully establish and develop despite the presence of T cells in tumour. An improved understanding of how tumours evade T-cell surveillance, coupled with technical developments allowing the culture and manipulation of T cells, has driven the exploration of therapeutic strategies based on the adoptive transfer of tumour-specific T cells. The isolation, expansion and re-infusion of large numbers of tumour-specific T cells generated from tumour biopsies has been shown to be feasible. Indeed, impressive clinical responses have been documented in melanoma patients treated with these T cells. These studies and others demonstrate the potential of T cells for the adoptive therapy of cancer. However, the significant technical issues relating to the production of natural tumour-specific T cells suggest that the application of this approach is likely to be limited at the moment. With the advent of retroviral gene transfer technology, it has become possible to efficiently endow T cells with antigen-specific receptors. Using this strategy, it is potentially possible to generate large numbers of tumour reactive T cells rapidly. This review summarises the current gene therapy approaches in relation to the development of adoptive T-cell-based cancer treatments, as these methods now head towards testing in the clinical trial setting.

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Related in: MedlinePlus

The chimeric immune receptor. (A) The T-cell receptor composed of the α and β chains transmits its signal through the CD3 molecule (γ, ɛ, δ and ζ moieties) following interaction with MHC/epitope complex. This differs from the chimeric immune receptor (B) which is composed of an extracellular single chain antibody recognition domain connected to signalling moiety shown in this example as either the CD3 ζ molecule (C) or as a fusion receptor using the CD28 molecule proximal to the ζ moiety. Activation of the chimeric immune receptor can be initiated in the presence of tumour antigen in an MHC independent manner.
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fig2: The chimeric immune receptor. (A) The T-cell receptor composed of the α and β chains transmits its signal through the CD3 molecule (γ, ɛ, δ and ζ moieties) following interaction with MHC/epitope complex. This differs from the chimeric immune receptor (B) which is composed of an extracellular single chain antibody recognition domain connected to signalling moiety shown in this example as either the CD3 ζ molecule (C) or as a fusion receptor using the CD28 molecule proximal to the ζ moiety. Activation of the chimeric immune receptor can be initiated in the presence of tumour antigen in an MHC independent manner.

Mentions: T cells using CIRs to target cellular antigens depend on the introduction of a gene encoding the receptor into the T cell. The essential components of a CIR are an antigen targeting domain fused to an intracellular signalling domain anchored to the surface of the T cell by a transmembrane domain (Figure 2). The antigen binding domain most commonly involves a single chain antibody fragment (scFv) consisting of the antigen recognition components of a monoclonal antibody (Gross et al, 1989; Hawkins et al, 1998), although other protein domains have been successfully used (Mitsuyasu et al, 2000). The scFv maintains the specificity of the original antibody, but carries the advantage of small size suitable for expression as part of a CIR. The predominant requisite for the targeted tumour antigen is cell surface expression. Aside from this, the diversity of antigens targeted to date is extensive with the majority of cancer types represented (Table 1).


Engineering T cells for cancer therapy.

Mansoor W, Gilham DE, Thistlethwaite FC, Hawkins RE - Br. J. Cancer (2005)

The chimeric immune receptor. (A) The T-cell receptor composed of the α and β chains transmits its signal through the CD3 molecule (γ, ɛ, δ and ζ moieties) following interaction with MHC/epitope complex. This differs from the chimeric immune receptor (B) which is composed of an extracellular single chain antibody recognition domain connected to signalling moiety shown in this example as either the CD3 ζ molecule (C) or as a fusion receptor using the CD28 molecule proximal to the ζ moiety. Activation of the chimeric immune receptor can be initiated in the presence of tumour antigen in an MHC independent manner.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361500&req=5

fig2: The chimeric immune receptor. (A) The T-cell receptor composed of the α and β chains transmits its signal through the CD3 molecule (γ, ɛ, δ and ζ moieties) following interaction with MHC/epitope complex. This differs from the chimeric immune receptor (B) which is composed of an extracellular single chain antibody recognition domain connected to signalling moiety shown in this example as either the CD3 ζ molecule (C) or as a fusion receptor using the CD28 molecule proximal to the ζ moiety. Activation of the chimeric immune receptor can be initiated in the presence of tumour antigen in an MHC independent manner.
Mentions: T cells using CIRs to target cellular antigens depend on the introduction of a gene encoding the receptor into the T cell. The essential components of a CIR are an antigen targeting domain fused to an intracellular signalling domain anchored to the surface of the T cell by a transmembrane domain (Figure 2). The antigen binding domain most commonly involves a single chain antibody fragment (scFv) consisting of the antigen recognition components of a monoclonal antibody (Gross et al, 1989; Hawkins et al, 1998), although other protein domains have been successfully used (Mitsuyasu et al, 2000). The scFv maintains the specificity of the original antibody, but carries the advantage of small size suitable for expression as part of a CIR. The predominant requisite for the targeted tumour antigen is cell surface expression. Aside from this, the diversity of antigens targeted to date is extensive with the majority of cancer types represented (Table 1).

Bottom Line: These studies and others demonstrate the potential of T cells for the adoptive therapy of cancer.However, the significant technical issues relating to the production of natural tumour-specific T cells suggest that the application of this approach is likely to be limited at the moment.With the advent of retroviral gene transfer technology, it has become possible to efficiently endow T cells with antigen-specific receptors.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK, Department of Medical Oncology, University of Manchester, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Withington, Manchester, UK.

ABSTRACT
It is generally accepted that the immune system plays an important role in controlling tumour development. However, the interplay between tumour and immune system is complex, as demonstrated by the fact that tumours can successfully establish and develop despite the presence of T cells in tumour. An improved understanding of how tumours evade T-cell surveillance, coupled with technical developments allowing the culture and manipulation of T cells, has driven the exploration of therapeutic strategies based on the adoptive transfer of tumour-specific T cells. The isolation, expansion and re-infusion of large numbers of tumour-specific T cells generated from tumour biopsies has been shown to be feasible. Indeed, impressive clinical responses have been documented in melanoma patients treated with these T cells. These studies and others demonstrate the potential of T cells for the adoptive therapy of cancer. However, the significant technical issues relating to the production of natural tumour-specific T cells suggest that the application of this approach is likely to be limited at the moment. With the advent of retroviral gene transfer technology, it has become possible to efficiently endow T cells with antigen-specific receptors. Using this strategy, it is potentially possible to generate large numbers of tumour reactive T cells rapidly. This review summarises the current gene therapy approaches in relation to the development of adoptive T-cell-based cancer treatments, as these methods now head towards testing in the clinical trial setting.

Show MeSH
Related in: MedlinePlus