研究揭示CAR-T細胞繞過抗原逃逸的機制
美國馬薩諸塞州綜合醫(yī)院和哈佛醫(yī)學(xué)院Marcela V. Maus研究團隊發(fā)現(xiàn)，分泌雙特異性T細胞銜接體（BiTE）的嵌合抗原受體（CAR）-T細胞，可以繞過抗原逃逸而無明顯毒性的機制。相關(guān)論文于2019年9月發(fā)表在《自然—生物技術(shù)》上。
他們使用雙順反子構(gòu)建體以驅(qū)動EGFRvIII特異性CAR的表達，EGFRvIII是一種膠質(zhì)母細胞瘤特異性腫瘤抗原，以及針對EGFR的（BiTE）。EGFR是一種在膠質(zhì)母細胞瘤中頻繁過表達但在正常組織中也表達的抗原。CART.BiTE細胞分泌EGFR特異性BiTE，其重定向CAR-T細胞并募集未轉(zhuǎn)導(dǎo)的旁觀者T細胞對抗野生型EGFR。EGFRvIII特異性CAR-T細胞不能完全治療具有異源EGFRvIII表達的腫瘤，導(dǎo)致EGFRvIII陰性、EGFR陽性膠質(zhì)母細胞瘤的生長。然而，CART.BiTE細胞消除了膠質(zhì)母細胞瘤小鼠模型中的異源腫瘤。 BiTE-EGFR局部有效但在顱內(nèi)遞送CART.BiTE細胞后未檢測到系統(tǒng)效應(yīng)。與EGFR特異性CAR-T細胞不同，CART.BiTE細胞在體內(nèi)不會對人皮膚移植產(chǎn)生毒性。
研究人員介紹，由于異源靶抗原表達和缺乏針對單個抗原的CAR-T細胞靶向的抗原腫瘤的生長，CAR-T細胞療法用于實體瘤受到限制。
附：英文原文
Title: CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity
Author: Bryan D. Choi, Xiaoling Yu, Ana P. Castano, Amanda A. Bouffard, Andrea Schmidts, Rebecca C. Larson, Stefanie R. Bailey, Angela C. Boroughs, Matthew J. Frigault, Mark B. Leick, Irene Scarf, Curtis L. Cetrulo, Shadmehr Demehri, Brian V. Nahed, Daniel P. Cahill, Hiroaki Wakimoto, William T. Curry, Bob S. Carter, Marcela V. Maus
Issue&Volume:Volume 37 Issue 9
Abstract: Chimeric antigen receptor (CAR)-T-cell therapy for solid tumors is limited due to heterogeneous target antigen expression and outgrowth of tumors lacking the antigen targeted by CAR-T cells directed against single antigens. Here, we developed a bicistronic construct to drive expression of a CAR specific for EGFRvIII, a glioblastoma-specific tumor antigen, and a bispecific T-cell engager (BiTE) against EGFR, an antigen frequently overexpressed in glioblastoma but also expressed in normal tissues. CART.BiTE cells secreted EGFR-specific BiTEs that redirect CAR-T cells and recruit untransduced bystander T cells against wild-type EGFR. EGFRvIII-specific CAR-T cells were unable to completely treat tumors with heterogenous EGFRvIII expression, leading to outgrowth of EGFRvIII-negative, EGFR-positive glioblastoma. However, CART.BiTE cells eliminated heterogenous tumors in mouse models of glioblastoma. BiTE-EGFR was locally effective but was not detected systemically after intracranial delivery of CART.BiTE cells. Unlike EGFR-specific CAR-T cells, CART.BiTE cells did not result in toxicity against human skin grafts in vivo.
DOI: 10.1038/s41587-019-0192-1
Source: https://www.nature.com/articles/s41587-019-0192-1
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