HER2 amplification occurs in approximately 5% of colorectal cancer (CRC) cases and is associated only partially with clinical response to combined human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR)-targeted treatment. An alternative approach based on adoptive cell therapy using T cells engineered with anti-HER2 chimeric antigen receptor (CAR) proved to be toxic due to on-target/off-tumor activity. Here we describe a combinatorial strategy to safely target HER2 amplification and carcinoembryonic antigen (CEA) expression in CRC using a synNotch-CAR-based artificial regulatory network. The natural killer (NK) cell line NK-92 was engineered with an anti-HER2 synNotch receptor driving the expression of a CAR against CEA only when engaged. After being transduced and sorted for HER2-driven CAR expression, cells were cloned. The clone with optimal performances in terms of specificity and amplitude of CAR induction demonstrated significant activity and specifically against HER2-amplified (HER2amp)/CEA CRC models, with no effects on cells with physiological HER2 levels. The HER2-synNotch/CEA-CAR-NK system provides an innovative, scalable, and safe off-the-shelf cell therapy approach with potential against HER2amp CRC resistant or partially responsive to HER2/EGFR blockade.

中文翻译：

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HER2 synNotch/CEA-CAR 组合免疫疗法针对具有 HER2 扩增的结直肠癌的临床前疗效


HER2 扩增发生在大约 5% 的结直肠癌 (CRC) 病例中，并且仅部分与人表皮生长因子受体 2 (HER2)/表皮生长因子受体 (EGFR) 联合靶向治疗的临床反应相关。另一种基于采用抗 HER2 嵌合抗原受体 (CAR) 工程 T 细胞的过继细胞疗法的替代方法被证明由于在靶/脱肿瘤活性而具有毒性。在这里，我们描述了一种组合策略，使用基于 synNotch-CAR 的人工调控网络安全地靶向 CRC 中的 HER2 扩增和癌胚抗原 (CEA) 表达。自然杀伤 (NK) 细胞系 NK-92 采用抗 HER2 synNotch 受体进行工程改造，仅在接合时驱动针对 CEA 的 CAR 表达。转导并分选 HER2 驱动的 CAR 表达后，细胞被克隆。在 CAR 诱导的特异性和幅度方面具有最佳性能的克隆表现出显着的活性，特别是针对 HER2 扩增 (HER2amp)/CEA CRC 模型，对具有生理 HER2 水平的细胞没有影响。 HER2-synNotch/CEA-CAR-NK 系统提供了一种创新、可扩展且安全的现成细胞治疗方法，具有对抗 HER2amp CRC 耐药性或对 HER2/EGFR 阻断部分响应的潜力。