生长抑素受体2型（SSTR2）是生长抑素受体的五种亚型之一，在大多数胃肠胰神经内分泌肿瘤（GEP-NET）、垂体瘤、副神经节瘤、脑膜瘤以及肝细胞癌的表面过度表达和乳腺癌。嵌合抗原受体 (CAR) T 细胞经过基因工程改造，可表达人工 T 细胞激活结合物，在连接后产生针对目标抗原表达细胞的杀菌活性。适配器-CAR T 细胞通过 CAR 识别抗原结合分子上的标签，在 CAR 和靶细胞之间建立激活桥梁。我们假设一种名为 Octo-Fluo 的新型 SSTR2 荧光肽拮抗剂与抗 FITC 接头 CAR (AdFITC(E2)-CAR) T 细胞相结合，可能充当 CAR 之间的开关可调激活桥梁。和SSTR2表达靶细胞。体外研究证实了 Octo-Fluo 与 Bon1-SSTR2 mCherry-Luc 细胞的结合，但没有内化的证据。 AdFITC(E2)-CAR T 细胞在体外以 Octo-Fluo 浓度依赖性方式被激活并有效诱导 Bon1-SSTR2 细胞死亡。同样，在治疗环境中，AdFITC(E2)-CAR T 细胞与 Octo-Fluo 联合有效地浸润肿瘤并消除了免疫缺陷小鼠的 Bon1-SSTR2 肿瘤。 AdFITC(E2)-CAR T 细胞肿瘤浸润和杀菌活性均依赖于 Octo-Fluo 浓度，高剂量的 Octo-Fluo 可以独立地使 CAR 和 SSTR2 抗原饱和，从而导致肿瘤浸润和杀灭活性丧失。由于桥形成的丧失而产生杀菌活性。我们的研究结果表明，使用 AdFITC(E2)-CAR T 细胞与 Octo-Fluo 作为多功能、开关可调双特异性适配器，用于针对 SSTR2 阳性 NET 的靶向 CAR T 细胞免疫治疗的潜力。© 2024 。经泰勒许可出版

Somatostatin receptor type 2 (SSTR2) is one of the five subtypes of somatostatin receptors and is overexpressed on the surface of most gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs), pituitary tumors, paraganglioma, and meningioma, as well as hepatocellular carcinoma and breast cancer. Chimeric antigen receptor (CAR) T-cells are genetically engineered to express an artificial, T-cell activating binder, leading upon ligation to biocidal activity against target-antigen expressing cells. Adaptor-CAR T-cells recognize, via the CAR, a tag on an antigen-binding molecule, building an activating bridge between the CAR and the target cell. We hypothesized that a novel fluorescent-peptide antagonist of SSTR2, called Octo-Fluo, in combination with anti-FITC adaptor CAR (AdFITC(E2)-CAR) T-cells, may function as an on-off tunable activating bridge between the CAR and SSTR2 expressing target cells. In vitro studies confirmed the binding of Octo-Fluo to Bon1-SSTR2 mCherry-Luc cells without evidence of internalization. AdFITC(E2)-CAR T-cells were activated and efficiently induced Bon1-SSTR2 cell death in vitro, in an Octo-Fluo concentration-dependent manner. Similarly, AdFITC(E2)-CAR T-cells in combination with Octo-Fluo efficiently infiltrated the tumor and eliminated Bon1-SSTR2 tumors in immunodeficient mice in therapeutic settings. Both, AdFITC(E2)-CAR T-cell tumor infiltration and biocidal activity were Octo-Fluo concentration-dependent, with high doses of Octo-Fluo, saturating both the CAR and the SSTR2 antigen independently, leading to the loss of tumor infiltration and biocidal activity due to the loss of bridge formation. Our findings demonstrate the potential of using AdFITC(E2)-CAR T-cells with Octo-Fluo as a versatile, on-off tunable bispecific adaptor for targeted CAR T-cell immunotherapy against SSTR2-positive NETs.© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.