Generation of T cell responses against broad KRAS hotspot neoantigens for cell therapy or TCR discovery.

IF 4.3 Q1 BIOCHEMICAL RESEARCH METHODS

Cell Reports Methods Pub Date : 2025-05-19 Epub Date: 2025-05-12 DOI:10.1016/j.crmeth.2025.101049

Brandon P Conn, Jared L Dietze, Christian J Yee, Margaret M Hallisey, Irais Ortiz-Caraveo, Marit M van Buuren, Richard B Gaynor, Kendra C Foley, Jaewon Choi, Vikram R Juneja

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Abstract

Adoptive cell therapy (ACT) with T cells targeting Kirsten rat sarcoma (KRAS) neoantigens can drive anti-tumor immunity but has so far been focused on a small fraction of known KRAS neoantigens. Here, we develop a single process starting from peripheral blood that can prime and expand T cell responses ex vivo to any KRAS neoantigen based on each individual's human leukocyte antigen (HLA) profile. We conducted the process in 20 healthy donors and generated T cell responses to 46 of 47 evaluated neoantigens. We identified and cloned more than 150 KRAS T cell receptors (TCRs), with the strongest TCRs having similar potency to clinically active benchmark TCRs. T cells generated through this process were able to slow tumor growth in vitro and in vivo. The approach could be used as the basis for the development of an ex vivo primed therapeutic or to discover a library of TCRs against a broad range of KRAS neoantigens.

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产生针对广泛的KRAS热点新抗原的T细胞应答，用于细胞治疗或TCR的发现。

利用T细胞靶向Kirsten大鼠肉瘤（KRAS）新抗原的过继细胞疗法（ACT）可以驱动抗肿瘤免疫，但迄今为止只集中在一小部分已知的KRAS新抗原上。在这里，我们开发了一个从外周血开始的单一过程，该过程可以根据每个人的人类白细胞抗原（HLA）谱，在体外启动和扩大T细胞对任何KRAS新抗原的反应。我们在20名健康供体中进行了这一过程，并对47种评估的新抗原中的46种产生了T细胞反应。我们鉴定并克隆了150多个KRAS T细胞受体（TCRs），其中最强的TCRs与临床活性基准TCRs具有相似的效力。通过这一过程产生的T细胞能够在体外和体内减缓肿瘤的生长。该方法可作为开发体外引物治疗方法或发现针对多种KRAS新抗原的TCRs文库的基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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