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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

Illustration of the tumor microenvironment in prostate cancer bone metastases and means of improving chimeric antigen receptor (CAR) T cell therapy. To achieve trafficking of CAR T cells to prostate cancer bone metastases, T cells can be engineered with chemokine receptors to be attracted to factors secreted by tumor cells, tumor stroma, or the bone lesion. T cell infiltration is influenced by blood vessel quality at the metastatic site. Prostate cancer bone metastases have poor vessel quality with dysfunctional junctions. Therefore, treatment with antiangiogenic drugs may normalize the vasculature and improve CAR T cell infiltration. Another approach is to target antigens that are expressed specifically on the tumor vasculature, such as prostate-specific membrane antigen. Tumor cells, as well as fibroblasts and immune cells in the stroma, secrete various immunosuppressive cytokines and chemokines. Osteoclasts at the metastatic site also produce immunosuppressive transforming growth factor (TGF)-β. The constant activity of osteoblasts and osteoclasts (which create osteolytic and osteosclerotic lesions, respectively) severely remodels the microenvironment and hinders T cell function. Blocking osteolysis may help CAR T cell trafficking, and engineering dominant-negative TGF-β receptors or signal converter receptors into CAR T cells may improve their function. To further eliminate the sources of inhibitory cytokines, preconditioning therapy can deplete regulatory T cells (Tregs) and myeloid-derived suppressor cells. The inclusion of inducible interleukin (IL)-12 in CAR T cells creates a better environment for the T cells to work in and can activate bystander immunity to kill antigen-negative tumor cells. Radiotherapy induces antigen release and activation of bystander immunity. Androgen deprivation therapy can render tumor cells more sensitive to T cell killing. Because of the highly immunosuppressive environment, CAR T cells need sufficient costimulation; therefore, third-generation CARs may be preferable. IFN-γ interferon-γ
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Fig2: Illustration of the tumor microenvironment in prostate cancer bone metastases and means of improving chimeric antigen receptor (CAR) T cell therapy. To achieve trafficking of CAR T cells to prostate cancer bone metastases, T cells can be engineered with chemokine receptors to be attracted to factors secreted by tumor cells, tumor stroma, or the bone lesion. T cell infiltration is influenced by blood vessel quality at the metastatic site. Prostate cancer bone metastases have poor vessel quality with dysfunctional junctions. Therefore, treatment with antiangiogenic drugs may normalize the vasculature and improve CAR T cell infiltration. Another approach is to target antigens that are expressed specifically on the tumor vasculature, such as prostate-specific membrane antigen. Tumor cells, as well as fibroblasts and immune cells in the stroma, secrete various immunosuppressive cytokines and chemokines. Osteoclasts at the metastatic site also produce immunosuppressive transforming growth factor (TGF)-β. The constant activity of osteoblasts and osteoclasts (which create osteolytic and osteosclerotic lesions, respectively) severely remodels the microenvironment and hinders T cell function. Blocking osteolysis may help CAR T cell trafficking, and engineering dominant-negative TGF-β receptors or signal converter receptors into CAR T cells may improve their function. To further eliminate the sources of inhibitory cytokines, preconditioning therapy can deplete regulatory T cells (Tregs) and myeloid-derived suppressor cells. The inclusion of inducible interleukin (IL)-12 in CAR T cells creates a better environment for the T cells to work in and can activate bystander immunity to kill antigen-negative tumor cells. Radiotherapy induces antigen release and activation of bystander immunity. Androgen deprivation therapy can render tumor cells more sensitive to T cell killing. Because of the highly immunosuppressive environment, CAR T cells need sufficient costimulation; therefore, third-generation CARs may be preferable. IFN-γ interferon-γ

Mentions: Localized prostate cancer is curable by surgery; therefore, this review focuses on metastatic prostate cancer. Metastases of prostate cancer are commonly found in lymph nodes and bones. The microenvironment in the bone metastases poses a considerable challenge for the infiltrating CAR T cells (see Fig. 2). In particular, bone metastases are associated with aberrant angiogenesis [59]. To establish outgrowth, cancer cells may initiate angiogenesis at the site of metastasis by recruiting bone marrow-derived endothelial cells. Although increased tumor angiogenesis provides more vessels for potential trafficking of CAR T cells, the quality of the vessels is typically poor, and T cells are unable to efficiently infiltrate tumors, possibly because of vascular endothelial growth factor (VEGF) expression [60]. Growth factors implicated in angiogenesis are found at elevated levels in prostate cancer bone metastases compared with primary tumors [61]. VEGF has an important role in establishment and outgrowth of prostate cancer bone metastases, as reviewed by Roberts et al. [62]. Besides facilitating recognition and targeting of cancer cells to the bone and establishing new vasculature for tumor growth, VEGF may also affect T cell infiltration into bone metastases [60]. Improved responses to immunotherapy have been reported with treatment with angiogenesis inhibitors in doses that normalize the vasculature rather than destroying it [63–65]. In the light of these findings, vascular normalization may be important to improve CAR T cell efficacy in bone metastasis. Even when CAR T cells are able to migrate to the metastatic site, infiltration of T cells into the metastases may be impaired. When treating a metastatic breast cancer patient, Bernhard et al. [66] reported that disseminated cancer cells were targeted efficiently by human epidermal growth factor receptor 2 (Her2)-specific CAR T cells, but solid metastases failed to respond, and the tumors progressed. These studies emphasize the critical importance of conditioning the microenvironment for T cells.Fig. 2


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

Hillerdal V, Essand M - BioDrugs (2015)

Illustration of the tumor microenvironment in prostate cancer bone metastases and means of improving chimeric antigen receptor (CAR) T cell therapy. To achieve trafficking of CAR T cells to prostate cancer bone metastases, T cells can be engineered with chemokine receptors to be attracted to factors secreted by tumor cells, tumor stroma, or the bone lesion. T cell infiltration is influenced by blood vessel quality at the metastatic site. Prostate cancer bone metastases have poor vessel quality with dysfunctional junctions. Therefore, treatment with antiangiogenic drugs may normalize the vasculature and improve CAR T cell infiltration. Another approach is to target antigens that are expressed specifically on the tumor vasculature, such as prostate-specific membrane antigen. Tumor cells, as well as fibroblasts and immune cells in the stroma, secrete various immunosuppressive cytokines and chemokines. Osteoclasts at the metastatic site also produce immunosuppressive transforming growth factor (TGF)-β. The constant activity of osteoblasts and osteoclasts (which create osteolytic and osteosclerotic lesions, respectively) severely remodels the microenvironment and hinders T cell function. Blocking osteolysis may help CAR T cell trafficking, and engineering dominant-negative TGF-β receptors or signal converter receptors into CAR T cells may improve their function. To further eliminate the sources of inhibitory cytokines, preconditioning therapy can deplete regulatory T cells (Tregs) and myeloid-derived suppressor cells. The inclusion of inducible interleukin (IL)-12 in CAR T cells creates a better environment for the T cells to work in and can activate bystander immunity to kill antigen-negative tumor cells. Radiotherapy induces antigen release and activation of bystander immunity. Androgen deprivation therapy can render tumor cells more sensitive to T cell killing. Because of the highly immunosuppressive environment, CAR T cells need sufficient costimulation; therefore, third-generation CARs may be preferable. IFN-γ interferon-γ
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: Illustration of the tumor microenvironment in prostate cancer bone metastases and means of improving chimeric antigen receptor (CAR) T cell therapy. To achieve trafficking of CAR T cells to prostate cancer bone metastases, T cells can be engineered with chemokine receptors to be attracted to factors secreted by tumor cells, tumor stroma, or the bone lesion. T cell infiltration is influenced by blood vessel quality at the metastatic site. Prostate cancer bone metastases have poor vessel quality with dysfunctional junctions. Therefore, treatment with antiangiogenic drugs may normalize the vasculature and improve CAR T cell infiltration. Another approach is to target antigens that are expressed specifically on the tumor vasculature, such as prostate-specific membrane antigen. Tumor cells, as well as fibroblasts and immune cells in the stroma, secrete various immunosuppressive cytokines and chemokines. Osteoclasts at the metastatic site also produce immunosuppressive transforming growth factor (TGF)-β. The constant activity of osteoblasts and osteoclasts (which create osteolytic and osteosclerotic lesions, respectively) severely remodels the microenvironment and hinders T cell function. Blocking osteolysis may help CAR T cell trafficking, and engineering dominant-negative TGF-β receptors or signal converter receptors into CAR T cells may improve their function. To further eliminate the sources of inhibitory cytokines, preconditioning therapy can deplete regulatory T cells (Tregs) and myeloid-derived suppressor cells. The inclusion of inducible interleukin (IL)-12 in CAR T cells creates a better environment for the T cells to work in and can activate bystander immunity to kill antigen-negative tumor cells. Radiotherapy induces antigen release and activation of bystander immunity. Androgen deprivation therapy can render tumor cells more sensitive to T cell killing. Because of the highly immunosuppressive environment, CAR T cells need sufficient costimulation; therefore, third-generation CARs may be preferable. IFN-γ interferon-γ
Mentions: Localized prostate cancer is curable by surgery; therefore, this review focuses on metastatic prostate cancer. Metastases of prostate cancer are commonly found in lymph nodes and bones. The microenvironment in the bone metastases poses a considerable challenge for the infiltrating CAR T cells (see Fig. 2). In particular, bone metastases are associated with aberrant angiogenesis [59]. To establish outgrowth, cancer cells may initiate angiogenesis at the site of metastasis by recruiting bone marrow-derived endothelial cells. Although increased tumor angiogenesis provides more vessels for potential trafficking of CAR T cells, the quality of the vessels is typically poor, and T cells are unable to efficiently infiltrate tumors, possibly because of vascular endothelial growth factor (VEGF) expression [60]. Growth factors implicated in angiogenesis are found at elevated levels in prostate cancer bone metastases compared with primary tumors [61]. VEGF has an important role in establishment and outgrowth of prostate cancer bone metastases, as reviewed by Roberts et al. [62]. Besides facilitating recognition and targeting of cancer cells to the bone and establishing new vasculature for tumor growth, VEGF may also affect T cell infiltration into bone metastases [60]. Improved responses to immunotherapy have been reported with treatment with angiogenesis inhibitors in doses that normalize the vasculature rather than destroying it [63–65]. In the light of these findings, vascular normalization may be important to improve CAR T cell efficacy in bone metastasis. Even when CAR T cells are able to migrate to the metastatic site, infiltration of T cells into the metastases may be impaired. When treating a metastatic breast cancer patient, Bernhard et al. [66] reported that disseminated cancer cells were targeted efficiently by human epidermal growth factor receptor 2 (Her2)-specific CAR T cells, but solid metastases failed to respond, and the tumors progressed. These studies emphasize the critical importance of conditioning the microenvironment for T cells.Fig. 2

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