SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma.
SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma.
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SynNotch-CAR T细胞克服了治疗胶质母细胞瘤的特异性，异质性和持久性的挑战。
DOI：
10.1126/scitranslmed.abe7378
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发表时间：
2021-04-28
影响因子：
17.1
通讯作者：
Lim WA
中科院分区：
文献类型：
--
作者：
Choe JH;Watchmaker PB;Simic MS;Gilbert RD;Li AW;Krasnow NA;Downey KM;Yu W;Carrera DA;Celli A;Cho J;Briones JD;Duecker JM;Goretsky YE;Dannenfelser R;Cardarelli L;Troyanskaya O;Sidhu SS;Roybal KT;Okada H;Lim WA
用嵌合抗原受体（CAR） T细胞治疗实体癌一直受到缺乏绝对肿瘤特异性和均匀表达的理想靶抗原的困扰。我们发现，在胶质母细胞瘤的背景下，多抗原启动和杀伤识别电路提供了灵活性和准确性，以克服这些挑战。一种synNotch受体可以识别特异性的启动抗原，如异质但肿瘤特异性的胶质母细胞瘤新抗原表皮生长因子受体剪接变体III （EGFRvIII）或中枢神经系统（CNS）组织特异性抗原髓鞘少突胶质细胞糖蛋白（MOG），可用于局部诱导CAR的表达。这使得彻底的，但控制肿瘤细胞杀死靶向抗原是同质的，但不是绝对的肿瘤特异性。此外，synnotch调控的CAR表达避免了补补性信号传导和耗竭，维持了更高比例的T细胞处于naïve/干细胞记忆状态。在携带异质表达EGFRvIII的脑内患者来源异种移植物（PDXs）的免疫缺陷小鼠中，单次静脉输注EGFRvIII synNotch-CAR - T细胞显示出比传统的组成性表达的CAR - T细胞更高的抗肿瘤功效和T细胞耐久性，而不会杀死肿瘤。由cns特异性抗原MOG引发的synNotch-CAR电路转导的T细胞也表现出对脑内PDX的精确和有效的控制，而没有证据表明在脑外启动。总之，通过使用整合多种不完善但互补抗原识别的电路，我们提高了针对胶质母细胞瘤的T细胞的特异性、完整性和持久性，提供了一种适用于其他实体肿瘤的通用识别策略。
Treatment of solid cancers with chimeric antigen receptor (CAR) T cells is plagued by the lack of ideal target antigens that are both absolutely tumor specific and homogeneously expressed. We show that multi-antigen prime-and-kill recognition circuits provide flexibility and precision to overcome these challenges in the context of glioblastoma. A synNotch receptor that recognizes a specific priming antigen, such as the heterogeneous but tumor-specific glioblastoma neoantigen epidermal growth factor receptor splice variant III (EGFRvIII) or the central nervous system (CNS) tissue-specific antigen myelin oligodendrocyte glycoprotein (MOG), can be used to locally induce expression of a CAR. This enables thorough but controlled tumor cell killing by targeting antigens that are homogeneous but not absolutely tumor specific. Moreover, synNotch-regulated CAR expression averts tonic signaling and exhaustion, maintaining a higher fraction of the T cells in a naïve/stem cell memory state. In immunodeficient mice bearing intracerebral patient-derived xenografts (PDXs) with heterogeneous expression of EGFRvIII, a single intravenous infusion of EGFRvIII synNotch-CAR T cells demonstrated higher antitumor efficacy and T cell durability than conventional constitutively expressed CAR T cells, without off-tumor killing. T cells transduced with a synNotch-CAR circuit primed by the CNS-specific antigen MOG also exhibited precise and potent control of intracerebral PDX without evidence of priming outside of the brain. In summary, by using circuits that integrate recognition of multiple imperfect but complementary antigens, we improve the specificity, completeness, and persistence of T cells directed against glioblastoma, providing a general recognition strategy applicable to other solid tumors.
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影响因子：
10.9
作者：
Ohno M;Ohkuri T;Kosaka A;Tanahashi K;June CH;Natsume A;Okada H
通讯作者：
Okada H
影响因子：
9.3
作者：
Dannenfelser R;Allen GM;VanderSluis B;Koegel AK;Levinson S;Stark SR;Yao V;Tadych A;Troyanskaya OG;Lim WA
通讯作者：
Lim WA
影响因子：
82.9
作者：
Long, Adrienne H.;Haso, Waleed M.;Shern, Jack F.;Wanhainen, Kelsey M.;Murgai, Meera;Ingaramo, Maria;Smith, Jillian P.;Walker, Alec J.;Kohler, M. Eric;Venkateshwara, Vikas R.;Kaplan, Rosandra N.;Patterson, George H.;Fry, Terry J.;Orentas, Rimas J.;Mackall, Crystal L.
通讯作者：
Mackall, Crystal L.
影响因子：
82.9
作者：
Gattinoni L;Lugli E;Ji Y;Pos Z;Paulos CM;Quigley MF;Almeida JR;Gostick E;Yu Z;Carpenito C;Wang E;Douek DC;Price DA;June CH;Marincola FM;Roederer M;Restifo NP
通讯作者：
Restifo NP
影响因子：
46.9
作者：
Choi, Bryan D.;Yu, Xiaoling;Maus, Marcela V.
通讯作者：
Maus, Marcela V.