Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada.
Front Immunol. 2022 Jul 6;13:905768. doi: 10.3389/fimmu.2022.905768. eCollection 2022.
Glioblastomas (GBM), the most common malignant primary adult brain tumors, are uniformly lethal and are in need of improved therapeutic modalities. GBM contain extensive regions of hypoxia and are enriched in therapy resistant brain tumor-initiating cells (BTICs). Carbonic anhydrase 9 (CA9) is a hypoxia-induced cell surface enzyme that plays an important role in maintenance of stem cell survival and therapeutic resistance. Here we demonstrate that CA9 is highly expressed in patient-derived BTICs. CA9 GBM BTICs showed increased self-renewal and proliferative capacity. To target CA9, we developed dual antigen T cell engagers (DATEs) that were exquisitely specific for CA9-positive patient-derived clear cell Renal Cell Carcinoma (ccRCC) and GBM cells. Combined treatment of either ccRCC or GBM cells with the CA9 DATE and T cells resulted in T cell activation, increased release of pro-inflammatory cytokines and enhanced cytotoxicity in a CA9-dependent manner. Treatment of ccRCC and GBM patient-derived xenografts markedly reduced tumor burden and extended survival. These data suggest that the CA9 DATE could provide a novel therapeutic strategy for patients with solid tumors expressing CA9 to overcome treatment resistance. .
胶质母细胞瘤（GBM）是最常见的恶性成人原发性脑肿瘤，普遍致命，需要改进治疗方式。GBM 含有广泛的缺氧区域，并富含对治疗有抗性的脑肿瘤起始细胞（BTICs）。碳酸酐酶 9（CA9）是一种缺氧诱导的细胞表面酶，在维持干细胞存活和治疗抗性方面发挥着重要作用。我们在这里证明，CA9 在患者来源的 BTICs 中高度表达。CA9 GBM BTICs 表现出更高的自我更新和增殖能力。为了靶向 CA9，我们开发了双抗原 T 细胞衔接器（DATE），其对 CA9 阳性的患者来源的透明细胞肾细胞癌（ccRCC）和 GBM 细胞具有极高的特异性。用 CA9 DATE 和 T 细胞联合治疗 ccRCC 或 GBM 细胞，可导致 T 细胞激活，以 CA9 依赖的方式增加促炎细胞因子的释放和增强细胞毒性。ccRCC 和 GBM 患者来源的异种移植的治疗显著降低了肿瘤负担并延长了生存时间。这些数据表明，CA9 DATE 可为表达 CA9 的实体瘤患者提供一种新的治疗策略，以克服治疗抗性。
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