Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA.
Texas Children's Cancer and Hematology Centers, Houston, Texas, USA.
Neuro Oncol. 2018 Mar 27;20(4):506-518. doi: 10.1093/neuonc/nox182.
Glioblastoma (GBM) is the most common primary malignant brain cancer, and is currently incurable. Chimeric antigen receptor (CAR) T cells have shown promise in GBM treatment. While we have shown that combinatorial targeting of 2 glioma antigens offsets antigen escape and enhances T-cell effector functions, the interpatient variability in surface antigen expression between patients hinders the clinical impact of targeting 2 antigen pairs. This study addresses targeting 3 antigens using a single CAR T-cell product for broader application.
We analyzed the surface expression of 3 targetable glioma antigens (human epidermal growth factor receptor 2 [HER2], interleukin-13 receptor subunit alpha-2 [IL13Rα2], and ephrin-A2 [EphA2]) in 15 primary GBM samples. Accordingly, we created a trivalent T-cell product armed with 3 CAR molecules specific for these validated targets encoded by a single universal (U) tricistronic transgene (UCAR T cells).
Our data showed that co-targeting HER2, IL13Rα2, and EphA2 could overcome interpatient variability by a tendency to capture nearly 100% of tumor cells in most tumors tested in this cohort. UCAR T cells made from GBM patients' blood uniformly expressed all 3 CAR molecules with distinct antigen specificity. UCAR T cells mediated robust immune synapses with tumor targets forming more polarized microtubule organizing centers and exhibited improved cytotoxicity and cytokine release over best monospecific and bispecific CAR T cells per patient tumor profile. Lastly, low doses of UCAR T cells controlled established autologous GBM patient derived xenografts (PDXs) and improved survival of treated animals.
UCAR T cells can overcome antigenic heterogeneity in GBM and lead to improved treatment outcomes.
胶质母细胞瘤（GBM）是最常见的原发性恶性脑癌，目前无法治愈。嵌合抗原受体（CAR）T 细胞在 GBM 治疗中显示出前景。虽然我们已经表明，针对 2 种神经胶质瘤抗原的组合靶向可以抵消抗原逃逸并增强 T 细胞效应功能，但患者之间表面抗原表达的个体间变异性阻碍了针对 2 种抗原对的靶向治疗的临床影响。本研究使用单个 CAR T 细胞产品针对 3 种抗原进行靶向治疗，以实现更广泛的应用。
我们分析了 15 个原发性 GBM 样本中 3 种可靶向神经胶质瘤抗原（人表皮生长因子受体 2 [HER2]、白细胞介素 13 受体亚单位 alpha-2 [IL13Rα2]和 EphA2）的表面表达。相应地，我们创建了一种三价 T 细胞产品，该产品配备了针对这些经验证靶点的 3 种 CAR 分子，这些靶点由单个通用（U）三顺反子转基因（UCAR T 细胞）编码。
我们的数据表明，通过靶向 HER2、IL13Rα2 和 EphA2 的共靶向作用，可以克服本研究队列中大多数肿瘤测试中的个体间变异性，倾向于捕获近 100%的肿瘤细胞。从 GBM 患者的血液中制备的 UCAR T 细胞均匀表达所有 3 种 CAR 分子，具有独特的抗原特异性。UCAR T 细胞与肿瘤靶标形成强大的免疫突触，形成更极化的微管组织中心，并表现出比每位患者肿瘤特征的最佳单特异性和双特异性 CAR T 细胞更好的细胞毒性和细胞因子释放。最后，低剂量的 UCAR T 细胞控制了已建立的自体 GBM 患者来源异种移植（PDX），并提高了治疗动物的存活率。
UCAR T 细胞可以克服 GBM 中的抗原异质性，并导致治疗效果的改善。
