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Chimeric antigen receptor-engineered T cells for the treatment of metastatic prostate cancer.

Hillerdal V, Essand M - BioDrugs (2015)

Bottom Line: Two main challenges that need to be resolved are how to increase the migration and infiltration of CAR T cells into prostate cancer bone metastases and how to counteract the immunosuppressive microenvironment found in bone lesions.Likewise, combination therapy with checkpoint inhibitors that can reduce tumor immunosuppression may help improve efficacy.Other elegant approaches such as induced expression of immune stimulatory cytokines upon target recognition may also help to recruit other effector immune cells to metastatic sites.

View Article: PubMed Central - PubMed

Affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 85, Uppsala, Sweden, Victoria.Hillerdal@igp.uu.se.

ABSTRACT
Cancer immunotherapy was selected as the Breakthrough of the Year 2013 by the editors of Science, in part because of the successful treatment of refractory hematological malignancies with adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells. Effective treatment of B cell leukemia may pave the road to future treatment of solid tumors, using similar approaches. The prostate expresses many unique proteins and, since the prostate gland is a dispensable organ, CAR T cells can potentially be used to target these tissue-specific antigens. However, the location and composition of prostate cancer metastases complicate the task of treating these tumors. It is therefore likely that more sophisticated CAR T cell approaches are going to be required for prostate metastasis than for B cell malignancies. Two main challenges that need to be resolved are how to increase the migration and infiltration of CAR T cells into prostate cancer bone metastases and how to counteract the immunosuppressive microenvironment found in bone lesions. Inclusion of homing (chemokine) receptors in CAR T cells may improve their recruitment to bone metastases, as may antibody-based combination therapies to normalize the tumor vasculature. Optimal activation of CAR T cells through the introduction of multiple costimulatory domains would help to overcome inhibitory signals from the tumor microenvironment. Likewise, combination therapy with checkpoint inhibitors that can reduce tumor immunosuppression may help improve efficacy. Other elegant approaches such as induced expression of immune stimulatory cytokines upon target recognition may also help to recruit other effector immune cells to metastatic sites. Although toxicities are difficult to predict in prostate cancer, severe on-target/off-tumor toxicities have been observed in clinical trials with use of CAR T cells against hematological malignancies; therefore, the choice of the target antigen is going to be crucial. This review focuses on different means of accomplishing maximal effectiveness of CAR T cell therapy for prostate cancer bone metastases while minimizing side effects and CAR T cell-associated toxicities. CAR T cell-based therapies for prostate cancer have the potential to be a therapy model for other solid tumors.

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Related in: MedlinePlus

The structures of a T cell receptor (TCR) and various-generation (gen) chimeric antigen receptors (CARs). The endogenous TCR α and β chain complex recognizes an antigenic peptide presented by a human leukocyte antigen (HLA) molecule on target cells. T cell signal transduction is mediated through the ζ chains of the CD3 complex (the immunoreceptor tyrosine-based activation motifs are depicted in yellow). To build an artificial CAR, an antibody-derived single-chain variable fragment with a light chain (VL) and a heavy chain (VH) is utilized for target recognition. To mimic natural TCR signaling, CARs are engineered with the intracellular activation domain of CD3-ζ for signal transduction. For sustained activation, persistence, and improved function, one or several costimulatory domains are added to create so-called second- and third-generation CARs. The most commonly used costimulatory domains are derived from CD28, 4-1BB, OX40, ICOS, and CD27. The costimulatory domains are connected to the extracellular part of the CAR via a transmembrane domain, most commonly derived from CD8 or CD28. To achieve flexibility, a hinge is incorporated in the CAR design
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Fig1: The structures of a T cell receptor (TCR) and various-generation (gen) chimeric antigen receptors (CARs). The endogenous TCR α and β chain complex recognizes an antigenic peptide presented by a human leukocyte antigen (HLA) molecule on target cells. T cell signal transduction is mediated through the ζ chains of the CD3 complex (the immunoreceptor tyrosine-based activation motifs are depicted in yellow). To build an artificial CAR, an antibody-derived single-chain variable fragment with a light chain (VL) and a heavy chain (VH) is utilized for target recognition. To mimic natural TCR signaling, CARs are engineered with the intracellular activation domain of CD3-ζ for signal transduction. For sustained activation, persistence, and improved function, one or several costimulatory domains are added to create so-called second- and third-generation CARs. The most commonly used costimulatory domains are derived from CD28, 4-1BB, OX40, ICOS, and CD27. The costimulatory domains are connected to the extracellular part of the CAR via a transmembrane domain, most commonly derived from CD8 or CD28. To achieve flexibility, a hinge is incorporated in the CAR design

Mentions: A CAR typically comprises an extracellular single-chain variable fragment (scFv) of an antibody for target recognition, a hinge region to provide flexibility for the scFv, a transmembrane region, and an intracellular signaling region. CARs are often referred to as first, second, or third generation, depending on their signaling moieties (see Fig. 1). First-generation CARs contain only the CD3-ζ chain, while second-generation CARs contain CD3-ζ and a domain from a costimulatory molecule—typically from CD28, 4-1BB, CD27, ICOS, or OX40—which augments the effect of CD3-ζ signaling. Third-generation CARs contain CD3-ζ and two costimulatory molecule domains. The center at Baylor College of Medicine performed side-by-side comparison of first- and second-generation CARs in patients with B cell lymphoma and found that CD28 costimulation was associated with enhanced persistence and survival of CAR-modified T cells [7]. Possibly even stronger activation can be obtained with third-generation CAR T cells [8–15], as they are capable of high proliferative responses in vivo, which may facilitate clinical responses. However, third-generation CAR T cells produce large amounts of cytokines, which could be associated with toxicity. To mediate efficient expression of CAR genes into T cells, different genetic platforms have been used to ensure integration of the transgene into the T cell genome and to ensure that the construct directs long-lasting expression of the CAR (see Box 2).Fig. 1


Chimeric antigen receptor-engineered T cells for the treatment of metastatic prostate cancer.

Hillerdal V, Essand M - BioDrugs (2015)

The structures of a T cell receptor (TCR) and various-generation (gen) chimeric antigen receptors (CARs). The endogenous TCR α and β chain complex recognizes an antigenic peptide presented by a human leukocyte antigen (HLA) molecule on target cells. T cell signal transduction is mediated through the ζ chains of the CD3 complex (the immunoreceptor tyrosine-based activation motifs are depicted in yellow). To build an artificial CAR, an antibody-derived single-chain variable fragment with a light chain (VL) and a heavy chain (VH) is utilized for target recognition. To mimic natural TCR signaling, CARs are engineered with the intracellular activation domain of CD3-ζ for signal transduction. For sustained activation, persistence, and improved function, one or several costimulatory domains are added to create so-called second- and third-generation CARs. The most commonly used costimulatory domains are derived from CD28, 4-1BB, OX40, ICOS, and CD27. The costimulatory domains are connected to the extracellular part of the CAR via a transmembrane domain, most commonly derived from CD8 or CD28. To achieve flexibility, a hinge is incorporated in the CAR design
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4544486&req=5

Fig1: The structures of a T cell receptor (TCR) and various-generation (gen) chimeric antigen receptors (CARs). The endogenous TCR α and β chain complex recognizes an antigenic peptide presented by a human leukocyte antigen (HLA) molecule on target cells. T cell signal transduction is mediated through the ζ chains of the CD3 complex (the immunoreceptor tyrosine-based activation motifs are depicted in yellow). To build an artificial CAR, an antibody-derived single-chain variable fragment with a light chain (VL) and a heavy chain (VH) is utilized for target recognition. To mimic natural TCR signaling, CARs are engineered with the intracellular activation domain of CD3-ζ for signal transduction. For sustained activation, persistence, and improved function, one or several costimulatory domains are added to create so-called second- and third-generation CARs. The most commonly used costimulatory domains are derived from CD28, 4-1BB, OX40, ICOS, and CD27. The costimulatory domains are connected to the extracellular part of the CAR via a transmembrane domain, most commonly derived from CD8 or CD28. To achieve flexibility, a hinge is incorporated in the CAR design
Mentions: A CAR typically comprises an extracellular single-chain variable fragment (scFv) of an antibody for target recognition, a hinge region to provide flexibility for the scFv, a transmembrane region, and an intracellular signaling region. CARs are often referred to as first, second, or third generation, depending on their signaling moieties (see Fig. 1). First-generation CARs contain only the CD3-ζ chain, while second-generation CARs contain CD3-ζ and a domain from a costimulatory molecule—typically from CD28, 4-1BB, CD27, ICOS, or OX40—which augments the effect of CD3-ζ signaling. Third-generation CARs contain CD3-ζ and two costimulatory molecule domains. The center at Baylor College of Medicine performed side-by-side comparison of first- and second-generation CARs in patients with B cell lymphoma and found that CD28 costimulation was associated with enhanced persistence and survival of CAR-modified T cells [7]. Possibly even stronger activation can be obtained with third-generation CAR T cells [8–15], as they are capable of high proliferative responses in vivo, which may facilitate clinical responses. However, third-generation CAR T cells produce large amounts of cytokines, which could be associated with toxicity. To mediate efficient expression of CAR genes into T cells, different genetic platforms have been used to ensure integration of the transgene into the T cell genome and to ensure that the construct directs long-lasting expression of the CAR (see Box 2).Fig. 1

Bottom Line: Two main challenges that need to be resolved are how to increase the migration and infiltration of CAR T cells into prostate cancer bone metastases and how to counteract the immunosuppressive microenvironment found in bone lesions.Likewise, combination therapy with checkpoint inhibitors that can reduce tumor immunosuppression may help improve efficacy.Other elegant approaches such as induced expression of immune stimulatory cytokines upon target recognition may also help to recruit other effector immune cells to metastatic sites.

View Article: PubMed Central - PubMed

Affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 85, Uppsala, Sweden, Victoria.Hillerdal@igp.uu.se.

ABSTRACT
Cancer immunotherapy was selected as the Breakthrough of the Year 2013 by the editors of Science, in part because of the successful treatment of refractory hematological malignancies with adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells. Effective treatment of B cell leukemia may pave the road to future treatment of solid tumors, using similar approaches. The prostate expresses many unique proteins and, since the prostate gland is a dispensable organ, CAR T cells can potentially be used to target these tissue-specific antigens. However, the location and composition of prostate cancer metastases complicate the task of treating these tumors. It is therefore likely that more sophisticated CAR T cell approaches are going to be required for prostate metastasis than for B cell malignancies. Two main challenges that need to be resolved are how to increase the migration and infiltration of CAR T cells into prostate cancer bone metastases and how to counteract the immunosuppressive microenvironment found in bone lesions. Inclusion of homing (chemokine) receptors in CAR T cells may improve their recruitment to bone metastases, as may antibody-based combination therapies to normalize the tumor vasculature. Optimal activation of CAR T cells through the introduction of multiple costimulatory domains would help to overcome inhibitory signals from the tumor microenvironment. Likewise, combination therapy with checkpoint inhibitors that can reduce tumor immunosuppression may help improve efficacy. Other elegant approaches such as induced expression of immune stimulatory cytokines upon target recognition may also help to recruit other effector immune cells to metastatic sites. Although toxicities are difficult to predict in prostate cancer, severe on-target/off-tumor toxicities have been observed in clinical trials with use of CAR T cells against hematological malignancies; therefore, the choice of the target antigen is going to be crucial. This review focuses on different means of accomplishing maximal effectiveness of CAR T cell therapy for prostate cancer bone metastases while minimizing side effects and CAR T cell-associated toxicities. CAR T cell-based therapies for prostate cancer have the potential to be a therapy model for other solid tumors.

Show MeSH
Related in: MedlinePlus