Preclinical In Vivo Modeling of Cytokine Release Syndrome Induced by ErbB-Retargeted Human T Cells: Identifying a Window of Therapeutic Opportunity?

Sjoukje Van Der Stegen; David M Davies; Scott Wilkie; Julie Foster; Jane Sosabowski; Jerome Burnet; Lynsey Whilding; Roseanna Petrovic; Sadaf Ghaem-Maghami; Stephen Mather; Jean-Pierre Jeannon; Ana Parente Pereira; John Maher

doi:10.4049/jimmunol.1301523

Preclinical In Vivo Modeling of Cytokine Release Syndrome Induced by ErbB-Retargeted Human T Cells: Identifying a Window of Therapeutic Opportunity?

Sjoukje Van Der Stegen, David M Davies, Scott Wilkie, Julie Foster, Jane Sosabowski, Jerome Burnet, Lynsey Whilding, Roseanna Petrovic, Sadaf Ghaem-Maghami, Stephen Mather, Jean-Pierre Jeannon, Ana Parente Pereira, John Maher^*

^*Corresponding author for this work

Comprehensive Cancer Centre

Research output: Contribution to journal › Article › peer-review

102 Citations (Scopus)

Abstract

The ErbB network is dysregulated in many solid tumors. To exploit this, we have developed a chimeric Ag receptor (CAR) named T1E28z that targets several pathogenetically relevant ErbB dimers. T1E28z is coexpressed with a chimeric cytokine receptor named 4αβ (combination termed T4), enabling the selective expansion of engineered T cells using IL-4. Human T4+ T cells exhibit antitumor activity against several ErbB+ cancer types. However, ErbB receptors are also expressed in several healthy tissues, raising concerns about toxic potential. In this study, we have evaluated safety of T4 immunotherapy in vivo using a SCID beige mouse model. We show that the human T1E28z CAR efficiently recognizes mouse ErbB+ cells, rendering this species suitable to evaluate preclinical toxicity. Administration of T4+ T cells using the i.v. or intratumoral routes achieves partial tumor regression without clinical or histopathologic toxicity. In contrast, when delivered i.p., tumor reduction is accompanied by dose-dependent side effects. Toxicity mediated by T4+ T cells results from target recognition in both tumor and healthy tissues, leading to release of both human (IL-2/IFN-γ) and murine (IL-6) cytokines. In extreme cases, outcome is lethal. Both toxicity and IL-6 release can be ameliorated by prior macrophage depletion, consistent with clinical data that implicate IL-6 in this pathogenic event. These data demonstrate that CAR-induced cytokine release syndrome can be modeled in mice that express target Ag in an appropriate distribution. Furthermore, our findings argue that ErbB-retargeted T cells can achieve therapeutic benefit in the absence of unacceptable toxicity, providing that route of administration and dose are carefully optimized.

Original language	English
Pages (from-to)	4589-4598
Number of pages	10
Journal	Journal of Immunology
Volume	191
Issue number	9
DOIs	https://doi.org/10.4049/jimmunol.1301523
Publication status	Published - 1 Nov 2013

Keywords

EPIDERMAL-GROWTH-FACTOR
CHIMERIC ANTIGEN RECEPTOR
EPITHELIAL OVARIAN-CANCER
NORMAL HUMAN ADULT
SCID BEIGE MICE
FACTOR-ALPHA
NEUREGULIN RECEPTOR
CARDIAC DEVELOPMENT
FETAL TISSUES
BREAST-CANCER

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Van Der Stegen, S., Davies, D. M., Wilkie, S., Foster, J., Sosabowski, J., Burnet, J., Whilding, L., Petrovic, R., Ghaem-Maghami, S., Mather, S., Jeannon, J-P., Parente Pereira, A., & Maher, J. (2013). Preclinical In Vivo Modeling of Cytokine Release Syndrome Induced by ErbB-Retargeted Human T Cells: Identifying a Window of Therapeutic Opportunity? Journal of Immunology, 191(9), 4589-4598. https://doi.org/10.4049/jimmunol.1301523

@article{1f41f89f1dc74183b5d85fc7992fe679,

title = "Preclinical In Vivo Modeling of Cytokine Release Syndrome Induced by ErbB-Retargeted Human T Cells: Identifying a Window of Therapeutic Opportunity?",

abstract = "The ErbB network is dysregulated in many solid tumors. To exploit this, we have developed a chimeric Ag receptor (CAR) named T1E28z that targets several pathogenetically relevant ErbB dimers. T1E28z is coexpressed with a chimeric cytokine receptor named 4αβ (combination termed T4), enabling the selective expansion of engineered T cells using IL-4. Human T4+ T cells exhibit antitumor activity against several ErbB+ cancer types. However, ErbB receptors are also expressed in several healthy tissues, raising concerns about toxic potential. In this study, we have evaluated safety of T4 immunotherapy in vivo using a SCID beige mouse model. We show that the human T1E28z CAR efficiently recognizes mouse ErbB+ cells, rendering this species suitable to evaluate preclinical toxicity. Administration of T4+ T cells using the i.v. or intratumoral routes achieves partial tumor regression without clinical or histopathologic toxicity. In contrast, when delivered i.p., tumor reduction is accompanied by dose-dependent side effects. Toxicity mediated by T4+ T cells results from target recognition in both tumor and healthy tissues, leading to release of both human (IL-2/IFN-γ) and murine (IL-6) cytokines. In extreme cases, outcome is lethal. Both toxicity and IL-6 release can be ameliorated by prior macrophage depletion, consistent with clinical data that implicate IL-6 in this pathogenic event. These data demonstrate that CAR-induced cytokine release syndrome can be modeled in mice that express target Ag in an appropriate distribution. Furthermore, our findings argue that ErbB-retargeted T cells can achieve therapeutic benefit in the absence of unacceptable toxicity, providing that route of administration and dose are carefully optimized.",

keywords = "EPIDERMAL-GROWTH-FACTOR, CHIMERIC ANTIGEN RECEPTOR, EPITHELIAL OVARIAN-CANCER, NORMAL HUMAN ADULT, SCID BEIGE MICE, FACTOR-ALPHA, NEUREGULIN RECEPTOR, CARDIAC DEVELOPMENT, FETAL TISSUES, BREAST-CANCER",

author = "{Van Der Stegen}, Sjoukje and Davies, {David M} and Scott Wilkie and Julie Foster and Jane Sosabowski and Jerome Burnet and Lynsey Whilding and Roseanna Petrovic and Sadaf Ghaem-Maghami and Stephen Mather and Jean-Pierre Jeannon and {Parente Pereira}, Ana and John Maher",

year = "2013",

month = nov,

day = "1",

doi = "10.4049/jimmunol.1301523",

language = "English",

volume = "191",

pages = "4589--4598",

journal = "Journal of Immunology",

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publisher = "American Association of Immunologists",

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Van Der Stegen, S, Davies, DM, Wilkie, S, Foster, J, Sosabowski, J, Burnet, J, Whilding, L, Petrovic, R, Ghaem-Maghami, S, Mather, S, Jeannon, J-P , Parente Pereira, A & Maher, J 2013, 'Preclinical In Vivo Modeling of Cytokine Release Syndrome Induced by ErbB-Retargeted Human T Cells: Identifying a Window of Therapeutic Opportunity?', Journal of Immunology, vol. 191, no. 9, pp. 4589-4598. https://doi.org/10.4049/jimmunol.1301523

TY - JOUR

T1 - Preclinical In Vivo Modeling of Cytokine Release Syndrome Induced by ErbB-Retargeted Human T Cells

T2 - Identifying a Window of Therapeutic Opportunity?

AU - Van Der Stegen, Sjoukje

AU - Davies, David M

AU - Wilkie, Scott

AU - Foster, Julie

AU - Sosabowski, Jane

AU - Burnet, Jerome

AU - Whilding, Lynsey

AU - Petrovic, Roseanna

AU - Ghaem-Maghami, Sadaf

AU - Mather, Stephen

AU - Jeannon, Jean-Pierre

AU - Parente Pereira, Ana

AU - Maher, John

PY - 2013/11/1

Y1 - 2013/11/1

N2 - The ErbB network is dysregulated in many solid tumors. To exploit this, we have developed a chimeric Ag receptor (CAR) named T1E28z that targets several pathogenetically relevant ErbB dimers. T1E28z is coexpressed with a chimeric cytokine receptor named 4αβ (combination termed T4), enabling the selective expansion of engineered T cells using IL-4. Human T4+ T cells exhibit antitumor activity against several ErbB+ cancer types. However, ErbB receptors are also expressed in several healthy tissues, raising concerns about toxic potential. In this study, we have evaluated safety of T4 immunotherapy in vivo using a SCID beige mouse model. We show that the human T1E28z CAR efficiently recognizes mouse ErbB+ cells, rendering this species suitable to evaluate preclinical toxicity. Administration of T4+ T cells using the i.v. or intratumoral routes achieves partial tumor regression without clinical or histopathologic toxicity. In contrast, when delivered i.p., tumor reduction is accompanied by dose-dependent side effects. Toxicity mediated by T4+ T cells results from target recognition in both tumor and healthy tissues, leading to release of both human (IL-2/IFN-γ) and murine (IL-6) cytokines. In extreme cases, outcome is lethal. Both toxicity and IL-6 release can be ameliorated by prior macrophage depletion, consistent with clinical data that implicate IL-6 in this pathogenic event. These data demonstrate that CAR-induced cytokine release syndrome can be modeled in mice that express target Ag in an appropriate distribution. Furthermore, our findings argue that ErbB-retargeted T cells can achieve therapeutic benefit in the absence of unacceptable toxicity, providing that route of administration and dose are carefully optimized.

AB - The ErbB network is dysregulated in many solid tumors. To exploit this, we have developed a chimeric Ag receptor (CAR) named T1E28z that targets several pathogenetically relevant ErbB dimers. T1E28z is coexpressed with a chimeric cytokine receptor named 4αβ (combination termed T4), enabling the selective expansion of engineered T cells using IL-4. Human T4+ T cells exhibit antitumor activity against several ErbB+ cancer types. However, ErbB receptors are also expressed in several healthy tissues, raising concerns about toxic potential. In this study, we have evaluated safety of T4 immunotherapy in vivo using a SCID beige mouse model. We show that the human T1E28z CAR efficiently recognizes mouse ErbB+ cells, rendering this species suitable to evaluate preclinical toxicity. Administration of T4+ T cells using the i.v. or intratumoral routes achieves partial tumor regression without clinical or histopathologic toxicity. In contrast, when delivered i.p., tumor reduction is accompanied by dose-dependent side effects. Toxicity mediated by T4+ T cells results from target recognition in both tumor and healthy tissues, leading to release of both human (IL-2/IFN-γ) and murine (IL-6) cytokines. In extreme cases, outcome is lethal. Both toxicity and IL-6 release can be ameliorated by prior macrophage depletion, consistent with clinical data that implicate IL-6 in this pathogenic event. These data demonstrate that CAR-induced cytokine release syndrome can be modeled in mice that express target Ag in an appropriate distribution. Furthermore, our findings argue that ErbB-retargeted T cells can achieve therapeutic benefit in the absence of unacceptable toxicity, providing that route of administration and dose are carefully optimized.

KW - EPIDERMAL-GROWTH-FACTOR

KW - CHIMERIC ANTIGEN RECEPTOR

KW - EPITHELIAL OVARIAN-CANCER

KW - NORMAL HUMAN ADULT

KW - SCID BEIGE MICE

KW - FACTOR-ALPHA

KW - NEUREGULIN RECEPTOR

KW - CARDIAC DEVELOPMENT

KW - FETAL TISSUES

KW - BREAST-CANCER

U2 - 10.4049/jimmunol.1301523

DO - 10.4049/jimmunol.1301523

M3 - Article

SN - 0022-1767

VL - 191

SP - 4589

EP - 4598

JO - Journal of Immunology

JF - Journal of Immunology

IS - 9

ER -

Preclinical In Vivo Modeling of Cytokine Release Syndrome Induced by ErbB-Retargeted Human T Cells: Identifying a Window of Therapeutic Opportunity?

Abstract

Keywords

UN SDGs

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