To widen the application of adoptive cell transfer using TILs from solid tumors, Kuilman et al. developed a functional genetic screening approach for identifying tumor-specific TCR genes from diagnostic biopsies, including from non-viable frozen tumor formats. Screening synthetic, high-complexity TCR libraries against multiplexed neoantigen gene expression libraries, neoantigen-reactive HLA class I- and II-restricted TCRs were detected with high sensitivity and specificity based on functional T cell activation. Neoantigen-specific TCRs were identified from melanoma and from low tumor mutational burden, microsatellite-stable colorectal carcinoma.
Contributed by Katherine Turner
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.
Author Info: (1) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. thomas.kuilman@astrazeneca.com. (2) Neogene Therapeutics, A member of the AstraZeneca Group
Author Info: (1) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. thomas.kuilman@astrazeneca.com. (2) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (3) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (4) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (5) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (6) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (7) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (8) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (9) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (10) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (11) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (12) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (13) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (14) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (15) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (16) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (17) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (18) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (19) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (20) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (21) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (22) Department of Pathology, Moffitt Cancer Center, Tampa, FL, USA. Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA. (23) Department of Pathology, Moffitt Cancer Center, Tampa, FL, USA. Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA. (24) Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA. Department of Immunology and Radiation Oncology Program, Moffitt Cancer Center, Tampa, FL, USA. (25) Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA. (26) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. (27) Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. (28) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (29) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands. (30) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (31) Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands. (32) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. (33) Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands. gavin.bendle@astrazeneca.com.
