Targeted delivery of tumor necrosis factor in combination with lomustine induces a T-cell dependent regression of glioblastoma

Glioblastoma is the most aggressive primary brain tumor with an unmet need for more effective therapies. Here we report that the combination of L19TNF, an antibody-cytokine fusion protein based on tumor necrosis factor that selectively localizes on the tumor neo-vasculature, with the alkylating agent lomustine, can induce tumor regression in orthotopic glioma-bearing mice and patients with recurrent glioblastoma. Mechanistically, this striking synergy crucially depended on T cells and involved activation of the tumor endothelium, tumor DNA damage, treatment-associated tumor necrosis, increased antigen presentation on MHC class I and tumor immune cell infiltration, as well as decreased tumor-associated immunosuppression. The clinical translation of this approach is ongoing, but already shows durable responses in the first recurrent glioblastoma patient cohort treated with L19TNF in combination with lomustine (NCT04573192).

胶质母细胞瘤（Glioblastoma）是侵袭性最强的原发性脑肿瘤，目前仍存在未被满足的更有效治疗需求。本研究报道，基于肿瘤坏死因子开发的抗体-细胞因子融合蛋白L19TNF可选择性定位于肿瘤新生血管，将其与烷化剂洛莫司汀联用，能够在原位胶质瘤荷瘤小鼠及复发性胶质母细胞瘤患者体内诱导肿瘤消退。机制研究显示，这种显著的协同效应关键依赖于T细胞，其涉及肿瘤内皮细胞激活、肿瘤DNA损伤、治疗相关性肿瘤坏死、主要组织相容性复合体I类（MHC class I）分子抗原递呈能力增强、肿瘤免疫细胞浸润增加，以及肿瘤相关免疫抑制状态的缓解。目前该疗法的临床转化研究正在推进中，但在首批接受L19TNF联合洛莫司汀治疗的复发性胶质母细胞瘤患者队列（NCT04573192）中已观察到持久应答。