肿瘤细胞治疗研究
英文原题：An αvβ6-specific virotherapy expressing bispecific immune cell activators induces immune cell activation to mediate tumor cell death.
Ad5 NULL-A20 是一种基于 5 型腺病毒的精准病毒疗法，经过工程化改造以选择性靶向 αvβ6 阳性肿瘤。
Ad5 NULL -A20 是一种基于 5 型腺病毒的精准病毒疗法，经工程化改造以选择性靶向 αv β 6 阳性肿瘤。双特异性免疫细胞激活剂（BICA）可同时结合免疫细胞受体和肿瘤细胞相关抗原（TAA），从而诱导肿瘤特异性免疫反应。将 Ad5 NULL -A20 的选择性和溶瘤特性与 BICA 的效力相结合，将产生一种更耐受、更持久的免疫细胞反应，且局限于肿瘤部位，从而减少脱靶效应和剂量限制性毒性。我们开发了多种 BICA，通过 CD3 靶向 T 细胞，通过 CD16/NKG2D 受体靶向自然杀伤（NK）细胞，并靶向 TAA 表皮生长因子受体（EGFR）和主要组织相容性复合体相关链 A（MICA）。体外研究证实，Ad5 NULL -A20 BICA 在 αv β 6 肿瘤细胞中导致肿瘤部位的 T 细胞和 NK 激活以及肿瘤细胞活力丧失。离体研究验证了这些发现，证明在存在 T 细胞或 NK 细胞的情况下，转导溶瘤 Ad5 NULL -A20-BICA 的患者来源 3D 肿瘤类器官生长显著且快速减少。表达 BICA 的 Ad5 NULL -A20 可产生强效免疫反应，导致肿瘤根除。该方法具有显著的转化潜力，可开发一种新型癌症治疗药物以取得临床成功。
Ad5 NULL -A20 is an adenovirus type 5-based precision virotherapy engineered to selectively target αv β 6-positive tumors. Bispecific immune cell activators (BICAs) bind both an immune cell receptor and tumor cell-associated antigen (TAA) in tandem to induce a tumor-specific immune response. Combining the selectivity and oncolytic properties of Ad5 NULL -A20 with the potency of BICA will create a more tolerated, enduring immune cell response limited to tumor sites, reducing off-target effects and dose-limiting toxicities. We developed multiple BICA targeting T cells via CD3, natural killer (NK) cells via CD16/NKG2D receptors, and TAA epidermal growth factor receptor (EGFR) and major histocompatibility complex-related chain A (MICA). In vitro studies establish that Ad5 NULL -A20 BICA in αv β 6 tumor cells results in T cell and NK activation at tumor sites and a loss of tumor cell viability. Ex vivo studies validate these findings demonstrating a significant and rapid reduction in growth of patient-derived 3D tumor organoids transduced with oncolytic Ad5 NULL -A20-BICA in the presence of T cells or NK cells. Ad5 NULL -A20 expressing BICA can produce a potent immune response resulting in tumor eradication. This approach has significant translational potential to develop a novel cancer therapeutic for clinical success.
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