肿瘤浸润淋巴细胞 (TIL) 的过继转移在黑色素瘤中显示出显着的效果，但在其他癌症中只有有限的临床益处，即使在 TIL 经过基因改造以改善其肿瘤归巢、细胞毒性潜力或克服细胞耗竭之后也是如此。所需的离体 TIL 扩增过程可能会引起 T 细胞克隆组成的变化，这可能会损害 TIL 制剂的肿瘤反应性并最终损害 TIL 治疗的成功。一种基于工程化 T 细胞（STAb-T 疗法）产生双特异性 T 细胞接合物 (TCE) 的有前途的方法提高了当前针对血液肿瘤中肿瘤相关抗原的 T 细胞重定向策略的功效。我们研究了非小细胞肺癌 (NSCLC) 肿瘤中的 TCRβ 库以及来自两名无关患者的离体扩增 TIL。我们生成了分泌抗表皮生长因子受体 (EGFR) × 抗 CD3 TCE (TILSTAb) 的 TIL，并使用 NSCLC 患者来源的异种移植 (PDX) 模型在体外和体内测试了它们的抗肿瘤功效，其中肿瘤碎片和 TIL 来自同一患者被移植到 hIL-2 NOG 小鼠中。我们证实，标准 TIL 扩增方案会促进肿瘤优势 T 细胞克隆的丢失和病毒反应性 TCR 克隆型的过度生长，而这些克隆型在原发性肿瘤中几乎无法检测到。我们在自体免疫人源化 PDX EGFR NSCLC 小鼠模型中进行瘤内和全身给药时，在体外和体内证明了 TILSTAb 的抗肿瘤活性，其中肿瘤消退是由带有非肿瘤显性克隆型的 TCE 重定向 CD4 TIL 介导的。© 2024作者。经泰勒许可出版

Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown remarkable results in melanoma, but only modest clinical benefits in other cancers, even after TIL have been genetically modified to improve their tumor homing, cytotoxic potential or overcome cell exhaustion. The required ex vivo TIL expansion process may induce changes in the T cell clonal composition, which could likely compromise the tumor reactivity of TIL preparations and ultimately the success of TIL therapy. A promising approach based on the production of bispecific T cell-engagers (TCE) by engineered T cells (STAb-T therapy) improves the efficacy of current T cell redirection strategies against tumor-associated antigens in hematological tumors. We studied the TCRβ repertoire in non-small cell lung cancer (NSCLC) tumors and in ex vivo expanded TIL from two unrelated patients. We generated TIL secreting anti-epidermal growth factor receptor (EGFR) × anti-CD3 TCE (TILSTAb) and tested their antitumor efficacy in vitro and in vivo using a NSCLC patient-derived xenograft (PDX) model in which tumor fragments and TIL from the same patient were transplanted into hIL-2 NOG mice. We confirmed that the standard TIL expansion protocol promotes the loss of tumor-dominant T cell clones and the overgrowth of virus-reactive TCR clonotypes that were marginally detectable in primary tumors. We demonstrated the antitumor activity of TILSTAb both in vitro and in vivo when administered intratumorally and systemically in an autologous immune-humanized PDX EGFR+ NSCLC mouse model, where tumor regression was mediated by TCE-redirected CD4+ TIL bearing non-tumor dominant clonotypes.© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.