Enabling next-generation engineered TCR-T therapies based on high-throughput TCR discovery from diagnostic tumor biopsies
Nature Communications, vol. 16, pp. 649
Abstract
Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) can mediate tumor regression, including complete and durable responses, in a range of solid cancers, most notably in melanoma. However, its wider application and efficacy has been restricted by the limited accessibility, proliferative capacity and effector function of tumor-specific TIL. Here, we develop a platform for the efficient identification of tumor-specific TCR genes from diagnostic tumor biopsies, including core-needle biopsies frozen in a non-viable format, to enable engineered T cell therapy. Using a genetic screening approach that detects antigen-reactive TCRs with high sensitivity and specificity based on T cell activation, we show that high complexity TCR libraries can be efficiently screened against multiplexed antigen libraries to identify both HLA class I and II restricted TCRs. Through the identification of neoantigen-specific TCRs directly from melanoma as well as low tumor mutational burden microsatellite-stable colorectal carcinoma samples, we demonstrate the pan-cancer potential of this platform. Kuilman et al. established a functional genetic screening platform for the efficient identification of tumor-specific TCRs. It is compatible with routine diagnostic tumor biopsies and can be applied in fully individualized TCR-T cell therapy.
Authors 31
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Thomas Kuilman corresponding
Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. thomas.kuilman@astrazeneca.com
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Affiliation as printed
Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA
Department of Pathology, Moffitt Cancer Center, Tampa, FL, USA
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Affiliation as printed
Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA
Department of Pathology, Moffitt Cancer Center, Tampa, FL, USA
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Affiliation as printed
Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA
Department of Immunology and Radiation Oncology Program, Moffitt Cancer Center, Tampa, FL, USA
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Affiliation as printed
Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA
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Leiden University Medical Center · AstraZeneca (Netherlands)
Affiliation as printed
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Leiden University Medical Center · The Netherlands Cancer Institute
Affiliation as printed
Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands
Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Leiden University Medical Center · The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands
Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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Gavin M. Bendle corresponding
Affiliation as printed
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. gavin.bendle@astrazeneca.com
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands
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