Kuilman Thomas, Schrikkema Deborah S, Gadiot Jules, Gomez-Eerland Raquel, Bies Laura, Walker Julia, Spaapen Robbert M, Kok Hanna, Houg Demi, Viyacheva Milena, Claassen Yvonne B, Saornil Manuel, Krijgsman Oscar, Stringer Bas, Ding Huiwen, Geleijnse Anou, Meinema Anne C, Weissbrich Bianca, Lancee Melissa, Engele Carmen G, Sabatino Marianna, Chen Pei-Ling, Tsai Kenneth Y, Mulé James J, Sondak Vernon K, van den Bulk Jitske, de Miranda Noel F, Jedema Inge, Haanen John G, van Heijst Jeroen W J, Schumacher Ton N, Linnemann Carsten, Bendle Gavin M
Neogene Therapeutics, A member of the AstraZeneca Group, Amsterdam, The Netherlands.
Department of Pathology, Moffitt Cancer Center, Tampa, FL, USA.
Nat Commun. 2025 Jan 14;16(1):649. doi: 10.1038/s41467-024-55420-6.
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.
采用肿瘤浸润淋巴细胞（TIL）进行过继性细胞疗法可介导多种实体癌发生肿瘤消退，包括完全且持久的反应，最显著的是在黑色素瘤中。然而，肿瘤特异性TIL的可及性有限、增殖能力和效应功能受限，限制了其更广泛的应用和疗效。在此，我们开发了一个平台，用于从诊断性肿瘤活检样本（包括以非存活形式冷冻的粗针活检样本）中高效鉴定肿瘤特异性TCR基因，以实现工程化T细胞疗法。我们使用一种基于T细胞活化、能高灵敏度和特异性检测抗原反应性TCR的基因筛选方法，表明可以针对多重抗原文库高效筛选高复杂性TCR文库，以鉴定HLA I类和II类限制性TCR。通过直接从黑色素瘤以及低肿瘤突变负担的微卫星稳定结直肠癌样本中鉴定新抗原特异性TCR，我们证明了该平台的泛癌潜力。
