IL-12非分泌型溶瘤病毒联合靶向B7-H4/NKG2D双特异性抗体协同抗肿瘤效应及其增效机制的研究

溶瘤病毒是极具开发潜力的肿瘤治疗策略，但单独应用时疗效维持时间短、仅能局部注射浅表肿瘤、收益人群小。近年来，肿瘤微环境免疫调控机制备受关注，其中MICA/NKG2D和B7-H4介导的通路分别参与微环境中NK细胞免疫激活和T细胞免疫抑制。课题组前期开发制备的IL-12非分泌型溶瘤腺病毒具有较好抑制肿瘤生长的作用，但疗效有限。本项目首次提出，将溶瘤腺病毒与靶向B7-H4/NKG2D双特异性抗体联合治疗肿瘤的新策略。该策略通过溶瘤病毒促进肿瘤抗原的释放和提呈，B7-H4单抗偶联MICA分子的双特异性抗体募集NKG2D阳性效应细胞到肿瘤病灶，再利用IL-12局部释放增强免疫细胞的效应。该策略实现局部杀伤肿瘤和免疫激活的双重目的，可有效杀伤B7-H4阳性肿瘤细胞，有望达到彻底清除肿瘤。本项目以期能够开发溶瘤病毒和双特异性抗体联合介导的NK细胞疗法，可增强溶瘤病毒的作用，提供长效稳定的抗肿瘤免疫效应。

Oncolytic virus is one of the most potential tumor immunotherapeutic strategies for development, but when used alone it has a short duration of efficacy, can only be injected locally into superficial tumors, and have a small benefit population. In recent years, much attention has been paid to the immune regulatory mechanisms of the tumor microenvironment, in which MICA/NKG2D and B7-H4-mediated pathways are involved in NK cell immune activation and T cell immune suppression, respectively. The oncolytic adenovirus armed with non-secreting IL-12 developed by our research group has a satisfactory efficacy in tumor inhibition, but its therapeutic effect is limited. This project proposes a novel strategy of combining oncolytic adenovirus with B7-H4/NKG2D-targeted bispecific antibody for tumor treatment. The strategy promotes the release and presentation of tumor antigens by oncolytic adenovirus. Bispecific antibody, consisted of B7-H4-targeted monoclonal antibody coupled with MICA molecule, recruits NKG2D-positive effector cells to the tumor lesion, and local release of IL-12 to enhance the activation of immunocytes. This strategy achieves both tumor local lysis and immune activation, it could effectively eliminate B7-H4-positive tumor cells, and is expected to achieve complete tumor clearance. This project aims to develop a combination-mediated NK cell therapy of oncolytic adenovirus and bispecific antibody that can enhance the efficiency of oncolytic adenovirus and provide a long-lasting and stable anti-tumor immunological effect.