Abstract
Successful CAR T cell therapy for the treatment of solid tumors requires exemplary CAR T cell expansion, persistence and fitness, and the ability to target tumor antigens safely. Here we address this constellation of critical attributes for successful cellular therapy by using integrated technologies that simplify development and derisk clinical translation. We have developed a CAR-CD19 T cell that secretes a CD19-anti-Her2 bridging protein. This cell therapy strategy exploits the ability of CD19-targeting CAR T cells to interact with CD19 on normal B cells to drive expansion, persistence and fitness. The secreted bridging protein potently binds to Her2-positive tumor cells, mediating CAR-CD19 T cell cytotoxicity in vitro and in vivo. Because of its short half-life, the secreted bridging protein will selectively accumulate at the site of highest antigen expression, ie. at the tumor. Bridging proteins that bind to multiple different tumor antigens have been created. Therefore, antigen-bridging CAR-CD19 T cells incorporate critical attributes for successful solid tumor cell therapy. This platform can be exploited to attack tumor antigens on any cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD19 / genetics*
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Antigens, CD19 / immunology
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B-Lymphocytes / immunology
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B-Lymphocytes / pathology
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Cell Line, Tumor
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Cell Proliferation
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Coculture Techniques
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Cytotoxicity, Immunologic
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ErbB Receptors / genetics
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ErbB Receptors / immunology
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Gene Expression
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Genetic Vectors / immunology
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Genetic Vectors / metabolism
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Humans
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Immunotherapy, Adoptive / methods*
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Lentivirus / genetics
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Lentivirus / immunology
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Lymphocyte Activation
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Lymphoma, B-Cell / genetics
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Lymphoma, B-Cell / immunology
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Lymphoma, B-Cell / pathology
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Lymphoma, B-Cell / therapy*
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Mice
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Mice, SCID
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Protein Binding
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Receptor, ErbB-2 / genetics*
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Receptor, ErbB-2 / immunology
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Receptors, Chimeric Antigen / genetics*
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Receptors, Chimeric Antigen / immunology
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology*
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Treatment Outcome
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Xenograft Model Antitumor Assays
Substances
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Antigens, CD19
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CD19 molecule, human
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Receptors, Chimeric Antigen
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EGFR protein, human
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ERBB2 protein, human
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ErbB Receptors
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Receptor, ErbB-2
Grants and funding
Aleta Biotherapeutics is wholly funded by Advent Life Science Partners, a venture capital firm. Therefore we would like to state the following – Advent Life Sciences did not play a role in the study design, data collection and analysis, decision to publish, or preparation of this manuscript and only provided financial support in the form of authors' salaries and/or research materials. The funder provided support in the form of salaries for authors [CA, LS, LW, FJD, AB, PDR], and paid consulting fees [RRL] but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.