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          Immunity:重大進展!利用新型CAR-T免疫療法治療實體瘤

                 2016年6月23日/生物谷BIOON/--嵌合抗原受體(chimeric antigen receptors, CAR)T細胞(CAR-T)是對病人自己的T細胞經過基因修飾而構建出的,在治療血癌上取得成功,但是利用CAR-T治療實體瘤并不那么成功,這是因為正常組織含有CAR-T靶向的蛋白,因而,CAR-T不僅攻擊腫瘤,也會攻擊正常組織。

                  如今,在一項新的研究中,來自美國賓夕法尼亞大學的研究人員描述了他們經過基因修飾設計出一種識別一種組合物--由一種已知的癌癥相關表面蛋白和一種癌癥相關糖分子組成---的CAR能夠用于CAR-T免疫療法中以便治療一系列實體瘤。他們在胰腺癌模式小鼠體內證實了這種新的CAR-T療法的有效性。相關研究結果于2016年6月21日在線發表在Immunity期刊上,論文標題為“Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma”。

                  論文第一作者兼論文共同通信作者Avery Posey博士說,“我們對T細胞進行基因修飾,讓它們靶向識別一種具有截斷的糖分子的癌癥相關表面蛋白。未來的癌癥免疫療法將T細胞對癌癥特異性的糖分子和癌蛋白的靶向識別能力結合起來,可能導致人們為癌癥患者開發出一種非常有效的和安全的新療法。這些經過基因改修飾的T細胞將能夠增加這種免疫療法的癌癥特異性和降低對病人的潛在毒性。”

                  一般而言,CAR-T免疫療法涉及通過一種類似于透析的方法從癌癥患者的血液中收集T細胞,然后對它們進行基因修飾,讓它們表達特定的CAR,而能夠識別癌細胞表面上的特異性分子。這些經過基因修飾的T細胞在灌注回患者體內后,能夠靶向殺死癌細胞。

                  在這項研究中,Posey、論文共同通信作者Laura Johnson博士和來自美國芝加哥大學和丹麥哥本哈根大學的同事們構建出表達特定CAR的CAR-T細胞,其中這種CAR特異性地識別粘蛋白1(MUC1)上截斷的糖分子。MUC1蛋白在正常的細胞表面上并不存在,但在很多類型的實體瘤和白血病的癌細胞表面上大量存在。

                  當將這些CAR-T細胞注射回白血病或胰腺癌小鼠體內后,這些腫瘤都萎縮了,而且在大多數小鼠中被消除了,從而導致存活期增加。在接受CAR-T治療后,胰腺癌小鼠仍然活了113天;然而,在接受不能夠靶向識別具有截斷的糖分子的MUC1蛋白的CAR-T治療的小鼠當中,在這項實驗結束時,僅有三分之一的小鼠存活下來。重要的是,這些經過基因修飾的CAR-T不能夠傷害正常的人細胞,也不能夠傷害不具有這種異常糖分子的細胞。

                  此外,利用高性能顯微鏡證實正常的細胞僅在細胞內部表達不成熟的癌癥相關的MUC1蛋白版本,然而,癌細胞將這種異常的蛋白運送到它的表面上,因此,這有助解釋為何這些經過基因修飾的CAR-T僅能夠識別腫瘤細胞表面上的這種癌癥特異性的蛋白。

                  這些發現提示著靶向識別在正常組織和實體瘤中發現的蛋白上存在的異常的癌癥特異性糖分子可能成為一種治療實體瘤的新免疫療法。這種腫瘤組合識別能力可能導致人們在未來為癌癥患者開發出一種安全的有效的療法。

                  Posey當前正在與哥本哈根大學同事Catharina Steentoft博士合作開發這種類型的新療法。Johnson說,“我們的研究證實這種新的癌癥靶向療法的安全性和有效性。我們正在其他的模型中繼續評估這種療法的安全性。一旦新的模型評估完畢,我們計劃將這種療法推向針對實體瘤患者的I期臨床試驗當中。”(生物谷 Bioon.com)
           

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