(1) Pellizzari G (2) Martinez O (3) Crescioli S (4) Page R (5) Di Meo A (6) Mele S (7) Chiaruttini G (8) Hoinka J (9) Batruch I (10) Prassas I (11) Grandits M (12) L—pez-Abente J (13) Bugallo-Blanco E (14) Ward M (15) Bax HJ (16) French E (17) Cheung A (18) Lombardi S (19) Figini M (20) Lacy KE (21) Diamandis EP (22) Josephs DH (23) Spicer J (24) Papa S (25) Karagiannis SN

Journal for immunotherapy of cancer

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-_ and 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.

Author Info: (1) St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, England, UK. (2) Immunoengineering Group, King's College London, Lon

Author Info: (1) St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, England, UK. (2) Immunoengineering Group, King's College London, London, England, UK. (3) St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, England, UK. (4) Immunoengineering Group, King's College London, London, England, UK. (5) Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. (6) St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, England, UK. (7) St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, England, UK. (8) Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA. (9) Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. (10) Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada. (11) St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, England, UK. (12) St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, England, UK. (13) Immunoengineering Group, King's College London, London, England, UK. (14) Aulesa Biosciences Ltd, Shefford, England, UK. (15) St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, England, UK. (16) St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, England, UK. (17) St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, England, UK. Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, King's College London, London, England, UK. (18) St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, England, UK. School of Cancer and Pharmaceutical Sciences, King's College London, London, England, UK. (19) Biomarker Unit, Dipartimento di Ricerca Applicata e Sviluppo Tecnologico (DRAST), Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. (20) St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, England, UK. (21) Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Department of Clinical Biochemistry, University Health Network, Toronto, Ontario, Canada. (22) St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, England, UK. Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, England, UK. (23) School of Cancer and Pharmaceutical Sciences, King's College London, London, England, UK. (24) Immunoengineering Group, King's College London, London, England, UK sophia.karagiannis@kcl.ac.uk sophie.papa@kcl.ac.uk. Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, England, UK. (25) St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, England, UK sophia.karagiannis@kcl.ac.uk sophie.papa@kcl.ac.uk. Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, King's College London, London, England, UK.

Citation: J Immunother Cancer 2021 Jun 9: Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/34112739

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