Immune inactivation of anti-simian immunodeficiency virus chimeric antigen receptor T cells in rhesus macaques.
Immune inactivation of anti-simian immunodeficiency virus chimeric antigen receptor T cells in rhesus macaques.
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DOI：
10.1016/j.omtm.2021.06.008
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发表时间：
2021-09-10
期刊：
影响因子：
--
通讯作者：
Corey L
中科院分区：
文献类型：
--
作者：
Haeseleer F;Fukazawa Y;Park H;Varco-Merth B;Rust BJ;Smedley JV;Eichholz K;Peterson CW;Mason R;Kiem HP;Roederer M;Picker LJ;Okoye AA;Corey L
嵌合抗原受体（CAR）T细胞疗法正在被研究作为潜在的HIV治愈方法，并被设计为靶向HIV储库。靶向猴免疫缺陷病毒（SIV）包膜的单克隆抗体（mAb）使我们能够研究基于单链可变片段（scFv）的抗SIV CAR T细胞的效力。在体外，表达针对SIV包膜的可变环1（V1）或V3的scFv的CAR T细胞在消除SIV感染的T细胞方面是高度有效的。然而，在临床前研究中，这些CAR T细胞在恒河猴（RM）中的体内输注导致缺乏扩增并且没有可检测的体内抗病毒活性。在CAR T细胞输注后1周注射表达嵌合抗原的抗原呈递细胞（APC）也未能刺激体内CAR T细胞扩增。为了研究这种体外与体内的差异，我们检查了针对CAR T细胞的宿主免疫应答。在输注抗SIV CAR T细胞后检测到针对CAR scFv的体液免疫应答; SIV感染动物血浆中存在的抗SIV IgG抗体与受抑制的CAR T细胞效应子功能相关。这些数据表明，CAR T细胞缺乏体内扩增和功效可能是由于抗体阻断了CAR scFv与其表位之间的相互作用。Corey及其同事评估了靶向猿免疫缺陷病毒包膜的CAR T细胞。他们表明，阻断CAR与其表位之间相互作用的抗体可能是导致抗SIV CAR T细胞体内增殖缺乏和在恒河猴中输注后杀死SIV感染细胞的原因。
Chimeric antigen receptor (CAR) T cell therapies are being investigated as potential HIV cures and designed to target HIV reservoirs. Monoclonal antibodies (mAbs) targeting the simian immunodeficiency virus (SIV) envelope allowed us to investigate the potency of single-chain variable fragment (scFv)-based anti-SIV CAR T cells. In vitro, CAR T cells expressing the scFv to both the variable loop 1 (V1) or V3 of the SIV envelope were highly potent at eliminating SIV-infected T cells. However, in preclinical studies, in vivo infusion of these CAR T cells in rhesus macaques (RMs) resulted in lack of expansion and no detectable in vivo antiviral activity. Injection of envelope-expressing antigen-presenting cells (APCs) 1 week post-CAR T cell infusion also failed to stimulate CAR T cell expansion in vivo. To investigate this in vitro versus in vivo discrepancy, we examined host immune responses directed at CAR T cells. A humoral immune response against the CAR scFv was detected post-infusion of the anti-SIV CAR T cells; anti-SIV IgG antibodies present in plasma of SIV-infected animals were associated with inhibited CAR T cell effector functions. These data indicate that lack of in vivo expansion and efficacy of CAR T cells might be due to antibodies blocking the interaction between the CAR scFv and its epitope. Corey and colleagues evaluated CAR T cells targeting the envelope of simian immunodeficiency virus. They show that antibodies blocking the interaction between the CAR and its epitope might be responsible for the lack of in vivo proliferation of anti-SIV CAR T cells and killing of SIV-infected cells after infusion in rhesus macaques.
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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
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：
82.9
作者：
Maldini, Colby R.;Claiborne, Daniel T.;Okawa, Ken;Chen, Tao;Dopkin, Derrick L.;Shan, Xiaochuan;Power, Karen A.;Trifonova, Radiana T.;Krupp, Katharine;Phelps, Meredith;Vrbanac, Vladimir D.;Tanno, Serah;Bateson, Timothy;Leslie, George J.;Hoxie, James A.;Boutwell, Christian L.;Riley, James L.;Allen, Todd M.
通讯作者：
Allen, Todd M.
影响因子：
5.4
作者：
Egelhofer, M;Brandenburg, G;von Laer, D
通讯作者：
von Laer, D
影响因子：
8.8
作者：
Aldon Y;McKay PF;Allen J;Ozorowski G;Felfödiné Lévai R;Tolazzi M;Rogers P;He L;de Val N;Fábián K;Scarlatti G;Zhu J;Ward AB;Crispin M;Shattock RJ
通讯作者：
Shattock RJ