SSTR2 as an anatomical imaging marker and a safety switch to monitor and manage CAR T cell toxicity.
SSTR2 as an anatomical imaging marker and a safety switch to monitor and manage CAR T cell toxicity.
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DOI：
10.1038/s41598-022-25224-z
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发表时间：
2022-12-03
影响因子：
4.6
通讯作者：
Jin, Moonsoo M.
中科院分区：
文献类型：
--
作者：
Alcaina, Yago;Yang, Yanping;Vedvyas, Yogindra;McCloskey, Jaclyn E.;Jin, Moonsoo M.
对体内过继转移的T细胞进行成像并消除它们以避免毒性的能力对于嵌合抗原受体(CAR)T细胞治疗至关重要，特别是针对具有较高非肿瘤毒性风险的实体肿瘤。此前，我们已经证明了生长抑素受体2(SSTR2)在CAR T细胞成像中的作用，说明了CAR T细胞在肿瘤内的扩张和收缩以及肿瘤外的扩张。以细胞间黏附分子1(ICAM-1)特异性CAR T细胞分泌白介素12(IL-12)为模型，我们研究了SSTR2与SSTR2特异性美坦辛-八曲酸偶联PEN-221结合时作为安全开关的潜力。IL-12的结构性分泌导致CAR T细胞在肿瘤快速消除后持续扩张，对MHC表达完整的小鼠造成全身毒性。PEN-221的治疗迅速降低了CAR T细胞的丰度，降低了异种移植物抗宿主病(GvHD)的严重程度，并延长了生存时间。我们的研究支持开发SSTR2作为CAR T细胞的单一遗传标记，该标记很容易适用于人类，既可用于解剖检测T细胞的分布，也可用于图像引导的安全开关以快速消除CAR T细胞。
The ability to image adoptively transferred T cells in the body and to eliminate them to avoid toxicity will be vital for chimeric antigen receptor (CAR) T cell therapy, particularly against solid tumors with higher risk of off-tumor toxicity. Previously, we have demonstrated the utility of somatostatin receptor 2 (SSTR2) for CAR T cell imaging, illustrating the expansion and contraction of CAR T cells in tumor as well as off-tumor expansion. Using intercellular adhesion molecule 1 (ICAM-1)-specific CAR T cells that secrete interleukin (IL)-12 as a model, herein we examined the potential of SSTR2 as a safety switch when combined with the SSTR2-specific maytansine-octreotate conjugate PEN-221. Constitutive secretion of IL-12 led to continuous expansion of CAR T cells after rapid elimination of tumors, causing systemic toxicity in mice with intact MHC expression. Treatment with PEN-221 rapidly reduced the abundance of CAR T cells, decreasing the severity of xenogeneic graft-versus-host disease (GvHD), and prolonged survival. Our study supports the development of SSTR2 as a single genetic marker for CAR T cells that is readily applicable to humans both for anatomical detection of T cell distribution and an image-guided safety switch for rapid elimination of CAR T cells.
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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：
13.6
作者：
Minn, Il;Huss, David J.;Pomper, Martin G.
通讯作者：
Pomper, Martin G.
影响因子：
20.3
作者：
Jacoby, Elad;Yang, Yinmeng;Fry, Terry J.
通讯作者：
Fry, Terry J.
影响因子：
82.9
作者：
Norelli, Margherita;Camisa, Barbara;Bondanza, Attilio
通讯作者：
Bondanza, Attilio
DOI：
10.2967/jnumed.113.134031
发表时间：
2014-05
期刊：
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
影响因子：
--
作者：
Castanares MA;Mukherjee A;Chowdhury WH;Liu M;Chen Y;Mease RC;Wang Y;Rodriguez R;Lupold SE;Pomper MG
通讯作者：
Pomper MG