Bayliss Rebecca J, Badder Luned M, Davies James, Robinson Andrew, Pissarreck Mona, Kollnberger Simon, Parker Alan L
Department of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Department of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Mol Ther Oncol. 2025 Jun 25;33(3):201017. doi: 10.1016/j.omton.2025.201017. eCollection 2025 Sep 18.
Ad5-A20 is an adenovirus type 5-based precision virotherapy engineered to selectively target αv6-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-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). studies establish that Ad5-A20 BICA in αv6 tumor cells results in T cell and NK activation at tumor sites and a loss of tumor cell viability. studies validate these findings demonstrating a significant and rapid reduction in growth of patient-derived 3D tumor organoids transduced with oncolytic Ad5-A20-BICA in the presence of T cells or NK cells. Ad5-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.
Ad5-A20是一种基于5型腺病毒的精准病毒疗法，经工程改造后可选择性靶向αv6阳性肿瘤。双特异性免疫细胞激活剂（BICA）串联结合免疫细胞受体和肿瘤细胞相关抗原（TAA），以诱导肿瘤特异性免疫反应。将Ad5-A20的选择性和溶瘤特性与BICA的效力相结合，将产生一种耐受性更好、持久的免疫细胞反应，且仅限于肿瘤部位，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，以及靶向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）。研究证实，αv6肿瘤细胞中的Ad5-A20 BICA可导致肿瘤部位的T细胞和NK细胞激活以及肿瘤细胞活力丧失。研究验证了这些发现，表明在T细胞或NK细胞存在的情况下，用溶瘤性Ad5-A20-BICA转导的患者来源的3D肿瘤类器官的生长显著且迅速减少。表达BICA的Ad5-A20可产生有效的免疫反应，从而根除肿瘤。这种方法在开发用于临床成功的新型癌症治疗方法方面具有重大的转化潜力。
