T Cells Engineered against a Native Antigen Can Surmount Immunologic and Physical Barriers to Treat Pancreatic Ductal Adenocarcinoma.
T Cells Engineered against a Native Antigen Can Surmount Immunologic and Physical Barriers to Treat Pancreatic Ductal Adenocarcinoma.
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DOI：
10.1016/j.ccell.2015.09.022
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发表时间：
2015-11-09
期刊：
影响因子：
50.3
通讯作者：
Hingorani SR
中科院分区：
文献类型：
--
作者：
Stromnes IM;Schmitt TM;Hulbert A;Brockenbrough JS;Nguyen H;Cuevas C;Dotson AM;Tan X;Hotes JL;Greenberg PD;Hingorani SR
胰腺导管腺癌（PDA）为化疗建立了物理屏障，并诱导多种免疫抑制机制，为不受阻碍的生长创造了庇护所。我们测试了T细胞的能力，工程化表达的亲和力增强的T细胞受体（TCR）对天然抗原，以克服这些障碍，在基因工程模型的本地PDA。工程化T细胞优先在PDA中积累并诱导肿瘤细胞死亡和基质重塑。然而，肿瘤浸润性T细胞变得逐渐功能失调，这一限制被连续T细胞输注成功克服，导致存活率几乎翻倍，而没有明显的毒性。类似地工程化的人T细胞在体外裂解PDA细胞，进一步支持用于治疗PDA的这种基于TCR的策略的临床进展。
Pancreatic ductal adenocarcinomas (PDA) erect physical barriers to chemotherapy and induce multiple mechanisms of immune suppression, creating a sanctuary for unimpeded growth. We tested the ability of T cells engineered to express an affinity-enhanced T cell receptor (TCR) against a native antigen to overcome these barriers in a genetically engineered model of autochthonous PDA. Engineered T cells preferentially accumulate in PDA and induce tumor cell death and stromal remodeling. However, tumor-infiltrating T cells become progressively dysfunctional, a limitation successfully overcome by serial T cell infusions that resulted in a near-doubling of survival without overt toxicities. Similarly engineered human T cells lyse PDA cells in vitro, further supporting clinical advancement of this TCR-based strategy for the treatment of PDA.