Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory.
Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory.
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DOI：
10.1073/pnas.1810060115
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发表时间：
2018-11-13
影响因子：
11.1
通讯作者：
Young TS
中科院分区：
文献类型：
--
作者：
Viaud S;Ma JSY;Hardy IR;Hampton EN;Benish B;Sherwood L;Nunez V;Ackerman CJ;Khialeeva E;Weglarz M;Lee SC;Woods AK;Young TS
嵌合抗原受体(CAR)T细胞治疗在免疫肿瘤学中代表着一种强有力的策略。然而，相关的危及生命的毒性和慢性B细胞再生障碍性疾病强调了控制患者体内工程T细胞的必要性。为了应对这些挑战，我们之前开发了一种可切换CAR(SCAR)T细胞平台，通过使用基于抗体的开关，允许对CAR T细胞活性进行剂量滴定控制。在这里，我们在同基因小鼠模型中证明了可切换平台可以传递抗肿瘤效果，同时将慢性B细胞再生障碍性贫血的长期持久性分离出来。此外，可切换平台的功能可逆性可被利用来通过对开关的循环给药来并入“休息”阶段，以使得能够诱导用于体内按需扩增SCAR T细胞的健壮的中央存储器群体。具有长寿命记忆表型的嵌合抗原受体(CAR)T细胞与白血病患者持久、完全缓解相关。然而，并不是所有的CAR T细胞产物都能形成强大的记忆力群体，而那些形成记忆群体的产品会导致患者的慢性B细胞再生障碍性贫血。为了应对这些挑战，我们之前开发了一种可切换CAR(SCAR)T细胞系统，允许对工程细胞活动进行完全可调的开/关控制。为了进一步评估该平台，我们生成并评估了不同的小鼠SCAR结构，以确定在一个有能力的免疫系统中提供SCAR T细胞的有效性、持久性和扩张性的因素。我们发现，SCAR T细胞在体内经历了显著的扩增，这与强大的抗肿瘤疗效有关。最重要的是，我们证明了切换给药方案不仅允许通过迭代耗尽和再繁殖来控制B细胞群，而且在给药周期之间的“休息”时期是诱导记忆和SCAR T细胞扩增的关键。这些发现介绍了REST作为一种增强记忆和改善T细胞工程产品的有效性和持久性的范例。
Chimeric antigen receptor (CAR) T cell therapy represents a powerful strategy in immuno-oncology. Nevertheless, associated life-threatening toxicities and chronic B cell aplasia have underscored the need to control engineered T cells in the patient. To address these challenges, we have previously developed a switchable CAR (sCAR) T cell platform that allows dose-titratable control over CAR T cell activity by using antibody-based switches. Here, we demonstrate in a syngeneic murine model that the switchable platform can impart antitumor efficacy while dissociating long-term persistence from chronic B cell aplasia. Further, the functional reversibility of the switchable platform can be leveraged to incorporate “rest” phases through cyclical dosing of the switch to enable the induction of a robust central memory population for in vivo, on-demand expansion of sCAR T cells. Chimeric antigen receptor (CAR) T cells with a long-lived memory phenotype are correlated with durable, complete remissions in patients with leukemia. However, not all CAR T cell products form robust memory populations, and those that do can induce chronic B cell aplasia in patients. To address these challenges, we previously developed a switchable CAR (sCAR) T cell system that allows fully tunable, on/off control over engineered cellular activity. To further evaluate the platform, we generated and assessed different murine sCAR constructs to determine the factors that afford efficacy, persistence, and expansion of sCAR T cells in a competent immune system. We find that sCAR T cells undergo significant in vivo expansion, which is correlated with potent antitumor efficacy. Most importantly, we show that the switch dosing regimen not only allows control over B cell populations through iterative depletion and repopulation, but that the “rest” period between dosing cycles is the key for induction of memory and expansion of sCAR T cells. These findings introduce rest as a paradigm in enhancing memory and improving the efficacy and persistence of engineered T cell products.
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影响因子：
10.1
作者：
Hudecek M;Sommermeyer D;Kosasih PL;Silva-Benedict A;Liu L;Rader C;Jensen MC;Riddell SR
通讯作者：
Riddell SR
DOI：
10.1097/cji.0b013e3181ac6138
发表时间：
2009-09
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
--
作者：
Kochenderfer JN;Feldman SA;Zhao Y;Xu H;Black MA;Morgan RA;Wilson WH;Rosenberg SA
通讯作者：
Rosenberg SA
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.
对子集进行分类：哪些 T 细胞群介导高效的过继免疫疗法？
DOI：
10.1097/cji.0b013e31827806e6
发表时间：
2012-11
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
--
作者：
Klebanoff CA;Gattinoni L;Restifo NP
通讯作者：
Restifo NP
影响因子：
3.7
作者：
Davila ML;Kloss CC;Gunset G;Sadelain M
通讯作者：
Sadelain M