Combining a CAR and a chimeric costimulatory receptor enhances T cell sensitivity to low antigen density and promotes persistence.
Combining a CAR and a chimeric costimulatory receptor enhances T cell sensitivity to low antigen density and promotes persistence.
复制标题
DOI：
10.1126/scitranslmed.abh1962
复制
发表时间：
2021-12-08
影响因子：
17.1
通讯作者：
Themeli, Maria
中科院分区：
文献类型：
--
作者：
Katsarou, Afroditi;Sjostrand, Maria;Naik, Jyoti;Mansilla-Soto, Jorge;Kefala, Dionysia;Kladis, Georgios;Nianias, Alexandros;Ruiter, Ruud;Poels, Renee;Sarkar, Irene;Patankar, Yash R.;Merino, Elena;Reijmers, Rogier M.;Frerichs, Kristine A.;Yuan, Huipin;de Bruijn, Joost;Stroopinsky, Dina;Avigan, David;van de Donk, Niels W. C. J.;Zweegman, Sonja;Mutis, Tuna;Sadelain, Michel;Groen, Richard W. J.;Themeli, Maria
尽管使用携带嵌合抗原受体（CAR）的T细胞针对血液恶性肿瘤实现了高缓解率，但仍有相当比例的患者最终经历肿瘤复发。临床研究已经确定，治疗失败的机制包括靶抗原表达的下调和有效CAR T细胞的持续性有限。我们假设由CAR和嵌合共刺激受体（CCR）介导的双重靶向可以同时增强T细胞的细胞毒性并改善耐久性。事实上，CD38结合CCR的伴随高亲和力接合通过增加BCMA和CD19-CAR T细胞的功能性结合亲合力来增强它们的细胞毒性。与第二代BCMA-或CD19-CAR T细胞相比，双靶向CAR + CD38-CCR T细胞在体外识别和裂解具有低抗原密度的多发性骨髓瘤（MM）和急性淋巴细胞白血病（ALL）的肿瘤变体的敏感性增加。此外，由CAR和CCR组合提供的4 - 1BB和CD28内域的互补共刺激赋予增加的细胞因子分泌和扩增，以及改善的体内持久性。值得注意的是，CAR + CCR T细胞的累积改善的特性使得能够在体内根除抗原低的肿瘤克隆，否则这些克隆对常规CAR T细胞的治疗具有抗性。因此，通过CAR和CCR的组合的多重靶向和共刺激是通过增强细胞毒性功效和持久性来改善CAR T细胞的临床结果的有力策略，从而防止具有低靶抗原密度的肿瘤克隆的复发。CAR和嵌合共刺激受体的组合增强T细胞的细胞毒性和耐久性，并消除抗原低的肿瘤。
Despite the high remission rates achieved using T cells bearing a chimeric antigen receptor (CAR) against hematogical malignancies, there is still a considerable proportion of patients who eventually experience tumor relapse. Clinical studies have established that mechanisms of treatment failure include the down-regulation of target antigen expression and the limited persistence of effective CAR T cells. We hypothesized that dual targeting mediated by a CAR and a chimeric costimulatory receptor (CCR) could simultaneously enhance T cell cytotoxity and improve durability. Indeed, concomitant high affinity engagement of a CD38-binding CCR enhanced the cytotoxicity of BCMA and CD19-CAR T cells by increasing their functional binding avidity. In comparison to second generation BCMA- or CD19-CAR T cells, double targeted CAR+CD38-CCR T cells exhibited increased sensitivity to recognize and lyse tumor variants of multiple myeloma (MM) and acute lymphoblastic leukemia (ALL) with low antigen density in vitro. Additionally, complimentary co-stimulation by 4-1BB and CD28 endodomains provided by the CAR and CCR combination conferred increased cytokine secretion and expansion, and improved persistence in vivo. Notably, the cumulatively improved properties of CAR+CCR T cells enabled the in vivo eradication of antigen-low tumor clones, which were otherwise resistant to treatment with conventional CAR T cells. Therefore, multiplexing targeting and co-stimulation through the combination of a CAR and a CCR is a powerful strategy to improve the clinical outcomes of CAR T cells by enhancing cytotoxic efficacy and persistence, thus preventing relapses of tumor clones with low target-antigen density. Combination of a CAR and a chimeric costimulatory receptor augments cytotoxicity and durability of T cells and eliminates of antigen-low tumors.
登录
查看更多内容
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.
DOI：
10.1016/j.iotech.2020.09.001
发表时间：
2020-12
期刊：
Immuno-oncology technology
影响因子：
--
作者：
Feucht, J;Sadelain, M
通讯作者：
Sadelain, M
影响因子：
7.3
作者：
Muller YD;Nguyen DP;Ferreira LMR;Ho P;Raffin C;Valencia RVB;Congrave-Wilson Z;Roth TL;Eyquem J;Van Gool F;Marson A;Perez L;Wells JA;Bluestone JA;Tang Q
通讯作者：
Tang Q
影响因子：
8.8
作者：
Kamsma, Douwe;Bochet, Pascal;Rose, Thierry
通讯作者：
Rose, Thierry
影响因子：
20.3
作者：
Green, Damian J.;O'Steen, Shyril;Press, Oliver W.
通讯作者：
Press, Oliver W.