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Clinical application of genetically modified T cells in cancer therapy.

Kershaw MH, Westwood JA, Slaney CY, Darcy PK - Clin Transl Immunology (2014)

Bottom Line: Recent methods of generating tumor-specific T cells include the genetic modification of patient lymphocytes with receptors to endow them with tumor specificity.These T cells are then expanded in vitro followed by infusion of the patient in adoptive cell transfer protocols.Genes used to modify T cells include those encoding T-cell receptors and chimeric antigen receptors.

View Article: PubMed Central - PubMed

Affiliation: Sir Peter MacCallum Cancer Centre, Department of Oncology, University of Melbourne , Melbourne, Victoria, Australia ; Department of Immunology, Monash University , Prahran, Victoria, Australia.

ABSTRACT
Immunotherapies are emerging as highly promising approaches for the treatment of cancer. In these approaches, a variety of materials are used to boost immunity against malignant cells. A key component of many of these approaches is functional tumor-specific T cells, but the existence and activity of sufficient T cells in the immune repertoire is not always the case. Recent methods of generating tumor-specific T cells include the genetic modification of patient lymphocytes with receptors to endow them with tumor specificity. These T cells are then expanded in vitro followed by infusion of the patient in adoptive cell transfer protocols. Genes used to modify T cells include those encoding T-cell receptors and chimeric antigen receptors. In this review, we provide an introduction to the field of genetic engineering of T cells followed by details of their use against cancer in the clinic.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of T cells genetically modified with tumor-reactive CARs or TCR. A tumor cell is shown (center) that expresses an antigen, which can be expressed in its native form on the cell surface or as peptide fragments in the context of major histocompatibility complex I (MHCI) molecules following processing intracellularly by the proteosome, endoplasmic reticulum (ER) and Golgi. (a) Cell surface antigen can be recognized by a CAR expressed by T cells. The CAR is composed of an extracellular single-chain antibody domain (scFv) linked by a hinge and transmembrane domains to several intracellular signaling domains, here represented by different colors. CARs are often expressed as dimers, as shown here. (b) Intracellularly processed antigen can be recognized by a transgene-encoded TCR expressed by T cells. The TCR associates with endogenous signaling molecules derived from the CD3 signaling complex.
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fig1: Schematic representation of T cells genetically modified with tumor-reactive CARs or TCR. A tumor cell is shown (center) that expresses an antigen, which can be expressed in its native form on the cell surface or as peptide fragments in the context of major histocompatibility complex I (MHCI) molecules following processing intracellularly by the proteosome, endoplasmic reticulum (ER) and Golgi. (a) Cell surface antigen can be recognized by a CAR expressed by T cells. The CAR is composed of an extracellular single-chain antibody domain (scFv) linked by a hinge and transmembrane domains to several intracellular signaling domains, here represented by different colors. CARs are often expressed as dimers, as shown here. (b) Intracellularly processed antigen can be recognized by a transgene-encoded TCR expressed by T cells. The TCR associates with endogenous signaling molecules derived from the CD3 signaling complex.

Mentions: There are two main types of antigen receptors used in genetic redirection (Figure 1). The first utilizes the native alpha and beta chains of a TCR specific for tumor antigen. The second is termed a chimeric antigen receptor (CAR), which is composed of an extracellular domain derived from tumor-specific antibody, linked to an intracellular signaling domain. Genes encoding these receptors are inserted into patients T cells using viral vectors to generate tumor-reactive T cells. This review briefly describes the nature of each type of receptor and its development, followed by a detailed description of the use of TCR and CAR transgenes in the clinic for cancer treatment, in addition to safety considerations and discussion of the future potential of this approach.


Clinical application of genetically modified T cells in cancer therapy.

Kershaw MH, Westwood JA, Slaney CY, Darcy PK - Clin Transl Immunology (2014)

Schematic representation of T cells genetically modified with tumor-reactive CARs or TCR. A tumor cell is shown (center) that expresses an antigen, which can be expressed in its native form on the cell surface or as peptide fragments in the context of major histocompatibility complex I (MHCI) molecules following processing intracellularly by the proteosome, endoplasmic reticulum (ER) and Golgi. (a) Cell surface antigen can be recognized by a CAR expressed by T cells. The CAR is composed of an extracellular single-chain antibody domain (scFv) linked by a hinge and transmembrane domains to several intracellular signaling domains, here represented by different colors. CARs are often expressed as dimers, as shown here. (b) Intracellularly processed antigen can be recognized by a transgene-encoded TCR expressed by T cells. The TCR associates with endogenous signaling molecules derived from the CD3 signaling complex.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232070&req=5

fig1: Schematic representation of T cells genetically modified with tumor-reactive CARs or TCR. A tumor cell is shown (center) that expresses an antigen, which can be expressed in its native form on the cell surface or as peptide fragments in the context of major histocompatibility complex I (MHCI) molecules following processing intracellularly by the proteosome, endoplasmic reticulum (ER) and Golgi. (a) Cell surface antigen can be recognized by a CAR expressed by T cells. The CAR is composed of an extracellular single-chain antibody domain (scFv) linked by a hinge and transmembrane domains to several intracellular signaling domains, here represented by different colors. CARs are often expressed as dimers, as shown here. (b) Intracellularly processed antigen can be recognized by a transgene-encoded TCR expressed by T cells. The TCR associates with endogenous signaling molecules derived from the CD3 signaling complex.
Mentions: There are two main types of antigen receptors used in genetic redirection (Figure 1). The first utilizes the native alpha and beta chains of a TCR specific for tumor antigen. The second is termed a chimeric antigen receptor (CAR), which is composed of an extracellular domain derived from tumor-specific antibody, linked to an intracellular signaling domain. Genes encoding these receptors are inserted into patients T cells using viral vectors to generate tumor-reactive T cells. This review briefly describes the nature of each type of receptor and its development, followed by a detailed description of the use of TCR and CAR transgenes in the clinic for cancer treatment, in addition to safety considerations and discussion of the future potential of this approach.

Bottom Line: Recent methods of generating tumor-specific T cells include the genetic modification of patient lymphocytes with receptors to endow them with tumor specificity.These T cells are then expanded in vitro followed by infusion of the patient in adoptive cell transfer protocols.Genes used to modify T cells include those encoding T-cell receptors and chimeric antigen receptors.

View Article: PubMed Central - PubMed

Affiliation: Sir Peter MacCallum Cancer Centre, Department of Oncology, University of Melbourne , Melbourne, Victoria, Australia ; Department of Immunology, Monash University , Prahran, Victoria, Australia.

ABSTRACT
Immunotherapies are emerging as highly promising approaches for the treatment of cancer. In these approaches, a variety of materials are used to boost immunity against malignant cells. A key component of many of these approaches is functional tumor-specific T cells, but the existence and activity of sufficient T cells in the immune repertoire is not always the case. Recent methods of generating tumor-specific T cells include the genetic modification of patient lymphocytes with receptors to endow them with tumor specificity. These T cells are then expanded in vitro followed by infusion of the patient in adoptive cell transfer protocols. Genes used to modify T cells include those encoding T-cell receptors and chimeric antigen receptors. In this review, we provide an introduction to the field of genetic engineering of T cells followed by details of their use against cancer in the clinic.

No MeSH data available.


Related in: MedlinePlus