克拉斯
癌症研究
肿瘤浸润淋巴细胞
抗原
T细胞受体
胰腺癌
生物
T细胞
免疫疗法
免疫学
免疫系统
癌症
突变
基因
遗传学
生物化学
作者
Sizhen Wang,Xiaohui Zhang,Xuemei Zou,Maorong Wen,Chi Gan,Xiaochun Jiang,Min Li,Rongxi Shen,Daxing Zhu,Anlong Yao,Fang Yu,Bernard A. Fox,Hong-Ming Hu,Guangjie Yu,Xinbo Wang
标识
DOI:10.1007/s00262-022-03335-w
摘要
Adoptive cell therapy (ACT) with expanded tumor-infiltrating lymphocytes (TIL) or TCR gene-modified T cells (TCR-T) that recognize mutant KRAS neo-antigens can mediate tumor regression in patients with advanced pancreatic ductal adenocarcinoma (PDAC) (Tran et al in N Engl J Med, 375:2255–2262, 2016; Leidner et al in N Engl J Med, 386:2112–2119, 2022). The mutant KRAS-targeted ACT holds great potential to achieve durable clinical responses for PDAC, which has had no meaningful improvement over 40 years. However, the wide application of mutant KRAS-centric ACT is currently limited by the rarity of TIL that recognize the mutant KRAS. In addition, PDAC is generally recognized as a poorly immunogenic tumor, and TILs in PDAC are less abundant than in immunogenic tumors such as melanoma. To increase the success rate of TIL production, we adopted a well-utilized K562-based artificial APC (aAPC) that expresses 4-1BBL as the costimulatory molecules to enhance the TIL production from PDCA. However, stimulation with K562-based aAPC led to a rapid loss of specificity to mutant KRAS. To selectively expand neo-antigen-specific T cells, particularly mKRAS, from the TILs, we used tandem mini gene-modified autologous T cells (TMG-T) as the novel aAPC. Using this modified IVS protocol, we successfully generated TIL cultures specifically reactive to mKRAS (G12V). We believe that autologous TMG-T cells provide a reliable source of autologous APC to expand a rare population of neoantigen-specific T cells in TILs.
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