Checkpoint Blockade Reverses Anergy in IL-13Rα2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas.
Checkpoint Blockade Reverses Anergy in IL-13Rα2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas.
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检查点封锁逆转基于 IL-13Rα2 人源化 scFv CAR T 细胞的无能性，用于治疗小鼠和犬神经胶质瘤
DOI：
10.1016/j.omto.2018.08.002
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发表时间：
2018-12-21
期刊：
影响因子：
--
通讯作者：
Johnson LA
中科院分区：
文献类型：
--
作者：
Yin Y;Boesteanu AC;Binder ZA;Xu C;Reid RA;Rodriguez JL;Cook DR;Thokala R;Blouch K;McGettigan-Croce B;Zhang L;Konradt C;Cogdill AP;Panjwani MK;Jiang S;Migliorini D;Dahmane N;Posey AD Jr;June CH;Mason NJ;Lin Z;O'Rourke DM;Johnson LA
我们产生了两种人源化白细胞介素-13受体α2（IL-13 R α2）嵌合抗原受体（汽车）Hu 07 BBz和Hu 08 BBz，它们识别人IL-13 R α2，但不识别IL-13 R α1。Hu 08 BBz还识别犬IL-13 R α2。这两种CAR T细胞构建体在人神经胶质瘤的皮下异种移植模型中均显示出与在最近的1期临床试验中使用的人源化EGFRvIII CAR T构建体相比的上级肿瘤抑制作用（ClinicalTrials.gov：NCT 02209376）。使用低剂量CAR T细胞输注，Hu 08 BBz显示原位肿瘤生长减少75%。使用与免疫检查点阻断的联合治疗，当与CTLA-4阻断组合时，人源化IL-13 R α2 CAR T细胞的表现显著更好，并且在相同的小鼠模型中，人源化EGFRvIII CAR T细胞的功效通过PD-1和TIM-3阻断而改善，这与体外与相同肿瘤共培养物中的检查点分子表达水平相关。人源化IL-13 R α2 CAR T细胞也在相同的小鼠模型中表现出自分泌抗CTLA-4微抗体的益处。除了犬神经胶质瘤细胞系（J3 T）外，犬骨肉瘤肺癌和白血病细胞系也表达IL-13 R α2，并被Hu 08 BBz识别。还生成了犬IL-13 R α2 CAR T细胞，并通过与犬肿瘤细胞共培养进行体外测试，并在犬神经胶质瘤原位模型中进行体内测试。基于这些结果，我们正在设计一项临床前试验，以评估犬IL-13 R α2 CAR T细胞在患有自发性IL-13 R α2阳性胶质瘤的犬中的安全性，这将有助于为使用基于人源化scFv的IL-13 R α2靶向CAR T细胞治疗胶质母细胞瘤的人类临床试验设计提供信息。
We generated two humanized interleukin-13 receptor α2 (IL-13Rα2) chimeric antigen receptors (CARs), Hu07BBz and Hu08BBz, that recognized human IL-13Rα2, but not IL-13Rα1. Hu08BBz also recognized canine IL-13Rα2. Both of these CAR T cell constructs demonstrated superior tumor inhibitory effects in a subcutaneous xenograft model of human glioma compared with a humanized EGFRvIII CAR T construct used in a recent phase 1 clinical trial (ClinicalTrials.gov: NCT02209376). The Hu08BBz demonstrated a 75% reduction in orthotopic tumor growth using low-dose CAR T cell infusion. Using combination therapy with immune checkpoint blockade, humanized IL-13Rα2 CAR T cells performed significantly better when combined with CTLA-4 blockade, and humanized EGFRvIII CAR T cells’ efficacy was improved by PD-1 and TIM-3 blockade in the same mouse model, which was correlated with the levels of checkpoint molecule expression in co-cultures with the same tumor in vitro. Humanized IL-13Rα2 CAR T cells also demonstrated benefit from a self-secreted anti-CTLA-4 minibody in the same mouse model. In addition to a canine glioma cell line (J3T), canine osteosarcoma lung cancer and leukemia cell lines also express IL-13Rα2 and were recognized by Hu08BBz. Canine IL-13Rα2 CAR T cell was also generated and tested in vitro by co-culture with canine tumor cells and in vivo in an orthotopic model of canine glioma. Based on these results, we are designing a pre-clinical trial to evaluate the safety of canine IL-13Rα2 CAR T cells in dog with spontaneous IL-13Rα2-positive glioma, which will help to inform a human clinical trial design for glioblastoma using humanized scFv-based IL-13Rα2 targeting CAR T cells.
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影响因子：
11.5
作者：
Kershaw, Michael H.;Westwood, Jennifer A.;Hwu, Patrick
通讯作者：
Hwu, Patrick
DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
45.3
作者：
Ahmed, Nabil;Brawley, Vita S.;Gottschalk, Stephen
通讯作者：
Gottschalk, Stephen
影响因子：
10.1
作者：
Anderson, Ana C.
通讯作者：
Anderson, Ana C.