Immunotherapy using IgE or CAR T cells for cancers expressing the tumor antigen SLC3A2

Giulia Pellizzari; Olivier Martinez; Silvia Crescioli; Robert Page; Ashley Di Meo; Silvia Mele; Giulia Chiaruttini; Jan Hoinka; Ihor Batruch; Ioannis Prassas; Melanie Grandits; Jacobo López-Abente; Eva Bugallo-Blanco; Malcolm Ward; Heather J Bax; Elise French; Anthony Cheung; Sara Lombardi; Mariangela Figini; Katie E Lacy; Eleftherios P Diamandis; Debra H Josephs; James Spicer; Sophie Papa; Sophia N Karagiannis

doi:10.1136/jitc-2020-002140

Immunotherapy using IgE or CAR T cells for cancers expressing the tumor antigen SLC3A2

Giulia Pellizzari, Olivier Martinez, Silvia Crescioli, Robert Page, Ashley Di Meo, Silvia Mele, Giulia Chiaruttini, Jan Hoinka, Ihor Batruch, Ioannis Prassas, Melanie Grandits, Jacobo López-Abente, Eva Bugallo-Blanco, Malcolm Ward, Heather J Bax, Elise French, Anthony Cheung, Sara Lombardi, Mariangela Figini, Katie E LacyEleftherios P Diamandis, Debra H Josephs, James Spicer, Sophie Papa, Sophia N Karagiannis

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Abstract

Background Cancer immunotherapy with monoclonal antibodies and chimeric antigen receptor (CAR) T cell therapies can benefit from selection of new targets with high levels of tumor specificity and from early assessments of efficacy and safety to derisk potential therapies. Methods Employing mass spectrometry, bioinformatics, immuno-mass spectrometry and CRISPR/Cas9 we identified the target of the tumor-specific SF-25 antibody. We engineered IgE and CAR T cell immunotherapies derived from the SF-25 clone and evaluated potential for cancer therapy. Results We identified the target of the SF-25 clone as the tumor-associated antigen SLC3A2, a cell surface protein with key roles in cancer metabolism. We generated IgE monoclonal antibody, and CAR T cell immunotherapies each recognizing SLC3A2. In concordance with preclinical and, more recently, clinical findings with the first-in-class IgE antibody MOv18 (recognizing the tumor-associated antigen Folate Receptor alpha), SF-25 IgE potentiated Fc-mediated effector functions against cancer cells in vitro and restricted human tumor xenograft growth in mice engrafted with human effector cells. The antibody did not trigger basophil activation in cancer patient blood ex vivo, suggesting failure to induce type I hypersensitivity, and supporting safe therapeutic administration. SLC3A2-specific CAR T cells demonstrated cytotoxicity against tumor cells, stimulated interferon-γand interleukin-2 production in vitro. In vivo SLC3A2-specific CAR T cells significantly increased overall survival and reduced growth of subcutaneous PC3-LN3-luciferase xenografts. No weight loss, manifestations of cytokine release syndrome or graft-versus-host disease, were detected. Conclusions These findings identify efficacious and potentially safe tumor-targeting of SLC3A2 with novel immune-activating antibody and genetically modified cell therapies.

Original language	English
Article number	e002140
Journal	Journal for ImmunoTherapy of Cancer
Volume	9
Issue number	6
DOIs	https://doi.org/10.1136/jitc-2020-002140 https://doi.org/10.1136/jitc-2020-002140
Publication status	Published - 11 Jun 2021

Keywords

Cancer Immunotherapy
CAR-T cell
tumor antigen
IgE
monoclonal antibody
AllergoOncology
cancer metabolism
SLC3A2
target identification

UN SDGs

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

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10.1136/jitc-2020-002140Licence: CC BY
10.1136/jitc-2020-002140

Immunotherapy using IgE or_PELLIZARI_Accepted25April2021_GOLD AAM (CC BY)Accepted author manuscript, 10.5 MBLicence: CC BY
Pellizzari Martinez et al JITC Published 11 June 2021Final published version, 7.05 MBLicence: CC BY

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Pellizzari, G., Martinez, O., Crescioli, S., Page, R., Di Meo, A., Mele, S., Chiaruttini, G., Hoinka, J., Batruch, I., Prassas, I., Grandits, M., López-Abente, J., Bugallo-Blanco, E., Ward, M., Bax, H. J., French, E., Cheung, A., Lombardi, S., Figini, M., ... Karagiannis, S. N. (2021). Immunotherapy using IgE or CAR T cells for cancers expressing the tumor antigen SLC3A2. Journal for ImmunoTherapy of Cancer, 9(6), Article e002140. https://doi.org/10.1136/jitc-2020-002140, https://doi.org/10.1136/jitc-2020-002140

@article{4fe780048a8046b8a956b388eaa71785,

title = "Immunotherapy using IgE or CAR T cells for cancers expressing the tumor antigen SLC3A2",

abstract = "Background Cancer immunotherapy with monoclonal antibodies and chimeric antigen receptor (CAR) T cell therapies can benefit from selection of new targets with high levels of tumor specificity and from early assessments of efficacy and safety to derisk potential therapies. Methods Employing mass spectrometry, bioinformatics, immuno-mass spectrometry and CRISPR/Cas9 we identified the target of the tumor-specific SF-25 antibody. We engineered IgE and CAR T cell immunotherapies derived from the SF-25 clone and evaluated potential for cancer therapy. Results We identified the target of the SF-25 clone as the tumor-associated antigen SLC3A2, a cell surface protein with key roles in cancer metabolism. We generated IgE monoclonal antibody, and CAR T cell immunotherapies each recognizing SLC3A2. In concordance with preclinical and, more recently, clinical findings with the first-in-class IgE antibody MOv18 (recognizing the tumor-associated antigen Folate Receptor alpha), SF-25 IgE potentiated Fc-mediated effector functions against cancer cells in vitro and restricted human tumor xenograft growth in mice engrafted with human effector cells. The antibody did not trigger basophil activation in cancer patient blood ex vivo, suggesting failure to induce type I hypersensitivity, and supporting safe therapeutic administration. SLC3A2-specific CAR T cells demonstrated cytotoxicity against tumor cells, stimulated interferon-γand interleukin-2 production in vitro. In vivo SLC3A2-specific CAR T cells significantly increased overall survival and reduced growth of subcutaneous PC3-LN3-luciferase xenografts. No weight loss, manifestations of cytokine release syndrome or graft-versus-host disease, were detected. Conclusions These findings identify efficacious and potentially safe tumor-targeting of SLC3A2 with novel immune-activating antibody and genetically modified cell therapies.",

keywords = "Cancer Immunotherapy, CAR-T cell, tumor antigen, IgE, monoclonal antibody, AllergoOncology, cancer metabolism, SLC3A2, target identification",

author = "Giulia Pellizzari and Olivier Martinez and Silvia Crescioli and Robert Page and {Di Meo}, Ashley and Silvia Mele and Giulia Chiaruttini and Jan Hoinka and Ihor Batruch and Ioannis Prassas and Melanie Grandits and Jacobo L{\'o}pez-Abente and Eva Bugallo-Blanco and Malcolm Ward and Bax, {Heather J} and Elise French and Anthony Cheung and Sara Lombardi and Mariangela Figini and Lacy, {Katie E} and Diamandis, {Eleftherios P} and Josephs, {Debra H} and James Spicer and Sophie Papa and Karagiannis, {Sophia N}",

note = "Funding Information: The authors acknowledge support by Breast Cancer Now (147; KCL-BCN-Q3); the Cancer Research UK King?s Health Partners Centre at King?s College London (C604/A25135); Cancer Research UK (C30122/A11527; C30122/A15774); the Medical Research Council (MR/L023091/1 and MR/L006278/1); CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587); the Inman Charity, the Guy?s and St Thomas?s Foundation Trust Charity Melanoma Special Fund (SPF573); The Academy of Medical Sciences and The Reece Foundation. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy?s and St Thomas' NHS Foundation Trust and King?s College London (IS-BRC- 1215-20006). Funding Information: Funding The authors acknowledge support by Breast Cancer Now (147; KCL-BCN-Q3); the Cancer Research UK King{\textquoteright}s Health Partners Centre at King{\textquoteright}s College London (C604/A25135); Cancer Research UK (C30122/A11527; C30122/A15774); the Medical Research Council (MR/L023091/1 and MR/L006278/1); CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587); the Inman Charity, the Guy{\textquoteright}s and St Thomas{\textquoteright}s Foundation Trust Charity Melanoma Special Fund (SPF573); The Academy of Medical Sciences and The Reece Foundation. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy{\textquoteright}s and St Thomas' NHS Foundation Trust and King{\textquoteright}s College London (IS-BRC-1215-20006). Publisher Copyright: {\textcopyright} 2021 Georg Thieme Verlag. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = jun,

day = "11",

doi = "10.1136/jitc-2020-002140",

language = "English",

volume = "9",

journal = "Journal for ImmunoTherapy of Cancer",

issn = "2051-1426",

publisher = "BioMed Central Ltd.",

number = "6",

}

Pellizzari, G , Martinez, O , Crescioli, S , Page, R, Di Meo, A, Mele, S , Chiaruttini, G, Hoinka, J, Batruch, I, Prassas, I, Grandits, M , López-Abente, J , Bugallo-Blanco, E, Ward, M, Bax, HJ, French, E, Cheung, A , Lombardi, S, Figini, M, Lacy, KE, Diamandis, EP, Josephs, DH , Spicer, J , Papa, S & Karagiannis, SN 2021, 'Immunotherapy using IgE or CAR T cells for cancers expressing the tumor antigen SLC3A2', Journal for ImmunoTherapy of Cancer, vol. 9, no. 6, e002140. https://doi.org/10.1136/jitc-2020-002140, https://doi.org/10.1136/jitc-2020-002140

TY - JOUR

T1 - Immunotherapy using IgE or CAR T cells for cancers expressing the tumor antigen SLC3A2

AU - Pellizzari, Giulia

AU - Martinez, Olivier

AU - Crescioli, Silvia

AU - Page, Robert

AU - Di Meo, Ashley

AU - Mele, Silvia

AU - Chiaruttini, Giulia

AU - Hoinka, Jan

AU - Batruch, Ihor

AU - Prassas, Ioannis

AU - Grandits, Melanie

AU - López-Abente, Jacobo

AU - Bugallo-Blanco, Eva

AU - Ward, Malcolm

AU - Bax, Heather J

AU - French, Elise

AU - Cheung, Anthony

AU - Lombardi, Sara

AU - Figini, Mariangela

AU - Lacy, Katie E

AU - Diamandis, Eleftherios P

AU - Josephs, Debra H

AU - Spicer, James

AU - Papa, Sophie

AU - Karagiannis, Sophia N

N1 - Funding Information: The authors acknowledge support by Breast Cancer Now (147; KCL-BCN-Q3); the Cancer Research UK King?s Health Partners Centre at King?s College London (C604/A25135); Cancer Research UK (C30122/A11527; C30122/A15774); the Medical Research Council (MR/L023091/1 and MR/L006278/1); CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587); the Inman Charity, the Guy?s and St Thomas?s Foundation Trust Charity Melanoma Special Fund (SPF573); The Academy of Medical Sciences and The Reece Foundation. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy?s and St Thomas' NHS Foundation Trust and King?s College London (IS-BRC- 1215-20006). Funding Information: Funding The authors acknowledge support by Breast Cancer Now (147; KCL-BCN-Q3); the Cancer Research UK King’s Health Partners Centre at King’s College London (C604/A25135); Cancer Research UK (C30122/A11527; C30122/A15774); the Medical Research Council (MR/L023091/1 and MR/L006278/1); CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587); the Inman Charity, the Guy’s and St Thomas’s Foundation Trust Charity Melanoma Special Fund (SPF573); The Academy of Medical Sciences and The Reece Foundation. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy’s and St Thomas' NHS Foundation Trust and King’s College London (IS-BRC-1215-20006). Publisher Copyright: © 2021 Georg Thieme Verlag. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/6/11

Y1 - 2021/6/11

N2 - Background Cancer immunotherapy with monoclonal antibodies and chimeric antigen receptor (CAR) T cell therapies can benefit from selection of new targets with high levels of tumor specificity and from early assessments of efficacy and safety to derisk potential therapies. Methods Employing mass spectrometry, bioinformatics, immuno-mass spectrometry and CRISPR/Cas9 we identified the target of the tumor-specific SF-25 antibody. We engineered IgE and CAR T cell immunotherapies derived from the SF-25 clone and evaluated potential for cancer therapy. Results We identified the target of the SF-25 clone as the tumor-associated antigen SLC3A2, a cell surface protein with key roles in cancer metabolism. We generated IgE monoclonal antibody, and CAR T cell immunotherapies each recognizing SLC3A2. In concordance with preclinical and, more recently, clinical findings with the first-in-class IgE antibody MOv18 (recognizing the tumor-associated antigen Folate Receptor alpha), SF-25 IgE potentiated Fc-mediated effector functions against cancer cells in vitro and restricted human tumor xenograft growth in mice engrafted with human effector cells. The antibody did not trigger basophil activation in cancer patient blood ex vivo, suggesting failure to induce type I hypersensitivity, and supporting safe therapeutic administration. SLC3A2-specific CAR T cells demonstrated cytotoxicity against tumor cells, stimulated interferon-γand interleukin-2 production in vitro. In vivo SLC3A2-specific CAR T cells significantly increased overall survival and reduced growth of subcutaneous PC3-LN3-luciferase xenografts. No weight loss, manifestations of cytokine release syndrome or graft-versus-host disease, were detected. Conclusions These findings identify efficacious and potentially safe tumor-targeting of SLC3A2 with novel immune-activating antibody and genetically modified cell therapies.

AB - Background Cancer immunotherapy with monoclonal antibodies and chimeric antigen receptor (CAR) T cell therapies can benefit from selection of new targets with high levels of tumor specificity and from early assessments of efficacy and safety to derisk potential therapies. Methods Employing mass spectrometry, bioinformatics, immuno-mass spectrometry and CRISPR/Cas9 we identified the target of the tumor-specific SF-25 antibody. We engineered IgE and CAR T cell immunotherapies derived from the SF-25 clone and evaluated potential for cancer therapy. Results We identified the target of the SF-25 clone as the tumor-associated antigen SLC3A2, a cell surface protein with key roles in cancer metabolism. We generated IgE monoclonal antibody, and CAR T cell immunotherapies each recognizing SLC3A2. In concordance with preclinical and, more recently, clinical findings with the first-in-class IgE antibody MOv18 (recognizing the tumor-associated antigen Folate Receptor alpha), SF-25 IgE potentiated Fc-mediated effector functions against cancer cells in vitro and restricted human tumor xenograft growth in mice engrafted with human effector cells. The antibody did not trigger basophil activation in cancer patient blood ex vivo, suggesting failure to induce type I hypersensitivity, and supporting safe therapeutic administration. SLC3A2-specific CAR T cells demonstrated cytotoxicity against tumor cells, stimulated interferon-γand interleukin-2 production in vitro. In vivo SLC3A2-specific CAR T cells significantly increased overall survival and reduced growth of subcutaneous PC3-LN3-luciferase xenografts. No weight loss, manifestations of cytokine release syndrome or graft-versus-host disease, were detected. Conclusions These findings identify efficacious and potentially safe tumor-targeting of SLC3A2 with novel immune-activating antibody and genetically modified cell therapies.

KW - Cancer Immunotherapy

KW - CAR-T cell

KW - tumor antigen

KW - IgE

KW - monoclonal antibody

KW - AllergoOncology

KW - cancer metabolism

KW - SLC3A2

KW - target identification

UR - http://www.scopus.com/inward/record.url?scp=85108044739&partnerID=8YFLogxK

U2 - 10.1136/jitc-2020-002140

DO - 10.1136/jitc-2020-002140

M3 - Article

C2 - 34112739

SN - 2051-1426

VL - 9

JO - Journal for ImmunoTherapy of Cancer

JF - Journal for ImmunoTherapy of Cancer

IS - 6

M1 - e002140

ER -

Immunotherapy using IgE or CAR T cells for cancers expressing the tumor antigen SLC3A2

Abstract

Keywords

UN SDGs

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