Discriminatory Power of Combinatorial Antigen Recognition in Cancer T Cell Therapies.
Discriminatory Power of Combinatorial Antigen Recognition in Cancer T Cell Therapies.
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DOI：
10.1016/j.cels.2020.08.002
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发表时间：
2020-09-23
期刊：
影响因子：
9.3
通讯作者：
Lim WA
中科院分区：
文献类型：
--
作者：
Dannenfelser R;Allen GM;VanderSluis B;Koegel AK;Levinson S;Stark SR;Yao V;Tadych A;Troyanskaya OG;Lim WA
肿瘤与正常组织的精确区分仍然是嵌合抗原受体（CAR）T细胞治疗功效的主要障碍。在这里，我们进行了一个全面的计算机屏幕，以确定多抗原的签名，提高肿瘤的区分CAR T细胞工程化整合多个抗原输入通过布尔逻辑，例如，和和不。我们在33种肿瘤类型和34种正常组织中筛选了> 250万个双重抗原和约6000万个三重抗原。我们发现，双重抗原显着优于最好的单一临床研究的CAR靶标，并通过实验证实了关键预测。此外，我们确定了预测显示出接近理想的肿瘤与正常组织区分几种肿瘤类型的抗原三联体。这项工作证明了2至3抗原布尔逻辑门通过CAR T细胞疗法改善肿瘤识别的潜力。我们的预测可在交互式网络服务器资源（antigen.princeton.edu）上获得。CAR T细胞在实体瘤中的应用受到难以识别单个靶抗原的限制，这些靶抗原足以区分肿瘤和正常组织以避免毒性。我们利用来自肿瘤和正常组织的大规模RNA-seq数据库来评估单个抗原和抗原组合的区分能力。大多数单一抗原，包括目前正在研究的实体瘤中作为CAR靶标的抗原，表现不佳。使用AND或NOT门控添加第二或第三抗原可以显著改善CAR T细胞性能。我们构建并测试了一对用于肾细胞癌的潜在AND门控T细胞。所有预测的高性能抗原对和三联体的完整数据库可在相关的网络服务器（antigen.princeton.edu）中获得。
Precise discrimination of tumor from normal tissues remains a major roadblock for therapeutic efficacy of chimeric antigen receptor (CAR) T cells. Here, we perform a comprehensive in silico screen to identify multi-antigen signatures that improve tumor discrimination by CAR T cells engineered to integrate multiple antigen inputs via Boolean logic, e.g., AND and NOT. We screen >2.5 million dual antigens and ~60 million triple antigens across 33 tumor types and 34 normal tissues. We find that dual antigens significantly outperform the best single clinically investigated CAR targets and confirm key predictions experimentally. Further, we identify antigen triplets that are predicted to show close to ideal tumor-versus-normal tissue discrimination for several tumor types. This work demonstrates the potential of 2- to 3-antigen Boolean logic gates for improving tumor discrimination by CAR T cell therapies. Our predictions are available on an interactive web server resource (antigen.princeton.edu). The application of CAR T cells to solid tumors is limited by the difficulty in identifying single target antigens that adequately discriminate between tumor and normal tissue to avoid toxicity. We leverage large-scale RNA-seq databases from tumor and normal tissues to evaluate the discriminatory power of single antigens and antigen combinations. Most single antigens, including those currently under investigation as CAR targets in solid tumors, perform poorly. The addition of a second or third antigen using AND or NOT gating can significantly improve CAR T cell performance. We construct and test a pair of potential AND-gated T cells for renal cell carcinoma. A full database of all predicted high-performing antigen pairs and triplets is made available in an associated web server (antigen.princeton.edu).
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遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
17.1
作者：
Fedorov VD;Themeli M;Sadelain M
通讯作者：
Sadelain M
DOI：
10.1007/s00262-017-2034-7
发表时间：
2017-11
期刊：
Cancer immunology, immunotherapy : CII
影响因子：
--
作者：
Thistlethwaite FC;Gilham DE;Guest RD;Rothwell DG;Pillai M;Burt DJ;Byatte AJ;Kirillova N;Valle JW;Sharma SK;Chester KA;Westwood NB;Halford SER;Nabarro S;Wan S;Austin E;Hawkins RE
通讯作者：
Hawkins RE
DOI：
10.1056/nejmoa1707447
发表时间：
2017-12-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Neelapu SS;Locke FL;Bartlett NL;Lekakis LJ;Miklos DB;Jacobson CA;Braunschweig I;Oluwole OO;Siddiqi T;Lin Y;Timmerman JM;Stiff PJ;Friedberg JW;Flinn IW;Goy A;Hill BT;Smith MR;Deol A;Farooq U;McSweeney P;Munoz J;Avivi I;Castro JE;Westin JR;Chavez JC;Ghobadi A;Komanduri KV;Levy R;Jacobsen ED;Witzig TE;Reagan P;Bot A;Rossi J;Navale L;Jiang Y;Aycock J;Elias M;Chang D;Wiezorek J;Go WY
通讯作者：
Go WY
影响因子：
2.9
作者：
Qu, Xiaohan;Liu, Jinlu;Zhang, Qigang
通讯作者：
Zhang, Qigang