Clonal expansion of T memory stem cells determines early anti-leukemic responses and long-term CAR T cell persistence in patients.
Clonal expansion of T memory stem cells determines early anti-leukemic responses and long-term CAR T cell persistence in patients.
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DOI：
10.1038/s43018-021-00207-7
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发表时间：
2021-06
期刊：
影响因子：
22.7
通讯作者：
Amrolia PJ
中科院分区：
文献类型：
--
作者：
Biasco L;Izotova N;Rivat C;Ghorashian S;Richardson R;Guvenel A;Hough R;Wynn R;Popova B;Lopes A;Pule M;Thrasher AJ;Amrolia PJ
低亲和力CD 19嵌合抗原受体（CAR）T细胞显示出增强的扩增和持久性，从而能够通过整合位点分析进行命运追踪。在这里，我们发现，整合位点从早期（1个月）和晚期（> 3年）的时间点聚类分开，表明不同的克隆贡献的早期反应和长期的抗白血病监测。长期持续性患者的CAR T中枢和效应记忆细胞保持高度多克隆，而在CAR T持续性有限的患者中，多样性迅速下降。CAR T细胞产物和输注后之间的共享整合体的分析表明，尽管其频率低，但产物中的T记忆干细胞克隆在早期扩增和长期持久性期间对循环CAR T细胞池有实质性贡献。我们的数据可能有助于识别有早期CAR T细胞丢失风险的患者，并强调T记忆干细胞在介导早期抗白血病反应和CAR T细胞长期监测中的关键作用。
Low-affinity CD19 chimeric antigen receptor (CAR) T cells display enhanced expansion and persistence, enabling fate tracking through integration site analysis. Here we show that integration sites from early (1 month) and late (>3yr) timepoints cluster separately, suggesting different clonal contribution to early responses and prolonged anti-leukemic surveillance. CAR T central and effector memory cells in patients with long-term persistence remained highly polyclonal, whereas diversity dropped rapidly in patients with limited CAR T persistence. Analysis of shared integrants between the CAR T cell product and post-infusion demonstrated that, despite their low frequency, T memory stem cell clones in the product contributed substantially to the circulating CAR T cell pools, during both early expansion and long-term persistence. Our data may help identify patients at risk of early loss of CAR T cells and highlight the critical role of T memory stem cells both in mediating early anti-leukemic responses and in long-term surveillance by CAR T cells.
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影响因子：
15.9
作者：
Berger, Carolina;Jensen, Michael C.;Riddell, Stanley R.
通讯作者：
Riddell, Stanley R.
影响因子：
20.3
作者：
Gardner, Rebecca A.;Finney, Olivia;Jensen, Michael C.
通讯作者：
Jensen, Michael C.
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
DOI：
10.1056/nejmoa1407222
发表时间：
2014-10-16
期刊：
The New England journal of medicine
影响因子：
--
作者：
Maude SL;Frey N;Shaw PA;Aplenc R;Barrett DM;Bunin NJ;Chew A;Gonzalez VE;Zheng Z;Lacey SF;Mahnke YD;Melenhorst JJ;Rheingold SR;Shen A;Teachey DT;Levine BL;June CH;Porter DL;Grupp SA
通讯作者：
Grupp SA