宾夕法尼亚大学佩雷尔曼医学院Daniel J. Powell研究团队近日取得一项新成果。经过不懈努力，他们报道了突变KRAS肽靶向CAR-T细胞用于癌症治疗。2025年6月5日，国际知名学术期刊《癌细胞》发表了这一成果。

研究人员利用多种遗传方法开发靶向肿瘤的CAR-T细胞疗法。首先，该研究团队筛选针对肽-MHC复合物呈现的致癌KRAS G12V突变的结合物。随后，该研究组将这些新抗原结合物结合到CAR-T细胞（mKRAS NeoCARs）中，并在转移性肺、胰腺和肾细胞癌的异种移植模型中证明了它们的有效性。最后，研究人员通过诱导分泌IL-12和T细胞受体缺失来增强mKRAS NeoCARs的体内疗效和安全性。总之，这些筛选和工程过程为扩大针对癌症的细胞免疫疗法的治疗指数提供了一个模块化平台。

据了解，尽管嵌合抗原受体(CAR)-T细胞治疗血液系统恶性肿瘤取得了成功，但由于治疗效果低或剂量限制性毒性，临床治疗实体肿瘤的成功受到限制。开发能够触发有效的、可控的、能够消除高度异质性和免疫抑制肿瘤细胞群的免疫反应的疗法仍然是一个关键的挑战。

附：英文原文

Title: Mutant KRAS peptide targeted CAR-T cells engineered for cancer therapy

Author: Alexander Benton, Jiageng Liu, Mathilde A. Poussin, Andrea Lang Goldgewicht, Madhara Udawela, Adham S. Bear, Nils Wellhausen, Beatriz M. Carreno, Pete M. Smith, Matthew D. Beasley, Ben R. Kiefel, Daniel J. Powell

Issue&Volume: 2025-06-05

Abstract: Despite the success of chimeric antigen receptor (CAR)-T cell therapies in hematological malignancies, clinical success against solid tumors is limited due to low therapeutic efficacy or dose-limiting toxicity. Developing therapies that trigger potent, yet manageable, immune responses capable of eliminating highly heterogeneous and immunosuppressive tumor cell populations remains a key challenge. Here, we harness multiple genetic approaches to develop a CAR-T cell therapy targeting tumors. First, we screen binders targeting oncogenic KRAS G12V mutations presented by peptide-MHC complexes. Subsequently, we incorporate these neoantigen binders into CAR-T cells (mKRAS NeoCARs) and demonstrate their efficacy in xenograft models of metastatic lung, pancreatic, and renal cell cancer. Finally, we enhance the in vivo efficacy and safety profile of mKRAS NeoCARs via inducible secretion of IL-12 and T cell receptor deletion. Together, these screening and engineering processes provide a modular platform for expanding the therapeutic index of cellular immunotherapies that target cancer.

DOI: 10.1016/j.ccell.2025.05.006

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00215-6