Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, CH-8091 Zurich, Switzerland.
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 4, CH-8093 Zürich, Switzerland.
Sci Transl Med. 2020 Oct 7;12(564). doi: 10.1126/scitranslmed.abb2311.
Glioblastoma is a poorly immunogenic cancer, and the successes with recent immunotherapies in extracranial malignancies have, so far, not been translated to this devastating disease. Therefore, there is an urgent need for new strategies to convert the immunologically cold glioma microenvironment into a hot one to enable effective antitumor immunity. Using the L19 antibody, which is specific to a tumor-associated epitope of extracellular fibronectin, we developed antibody-cytokine fusions-immunocytokines-with interleukin-2 (IL2), IL12, or tumor necrosis factor (TNF). We showed that L19 accumulated in the tumor microenvironment of two orthotopic immunocompetent mouse glioma models. Furthermore, intravenous administration of L19-mIL12 or L19-mTNF cured a proportion of tumor-bearing mice, whereas L19-IL2 did not. This therapeutic activity was abolished in RAG mice or upon depletion of CD4 or CD8 T cells, suggesting adaptive immunity. Mechanistically, both immunocytokines promoted tumor-infiltrating lymphocytes and increased the amounts of proinflammatory cytokines within the tumor microenvironment. In addition, L19-mTNF induced tumor necrosis. Systemic administration of the fully human L19-TNF fusion protein to patients with glioblastoma (NCT03779230) was safe, decreased regional blood perfusion within the tumor, and was associated with increasing tumor necrosis and an increase in tumor-infiltrating CD4 and CD8 T cells. The extensive preclinical characterization and subsequent clinical translation provide a robust basis for future studies with immunocytokines to treat malignant brain tumors.
胶质母细胞瘤是一种免疫原性较差的癌症，最近在颅外恶性肿瘤中免疫疗法的成功，迄今为止尚未转化为这种毁灭性疾病。因此，迫切需要新的策略将免疫原性冷的神经胶质瘤微环境转化为热环境，以实现有效的抗肿瘤免疫。我们使用针对细胞外纤维连接蛋白的肿瘤相关表位的 L19 抗体，开发了抗体-细胞因子融合物-免疫细胞因子，其中包含白细胞介素 2 (IL2)、白细胞介素 12 (IL12)或肿瘤坏死因子 (TNF)。我们表明，L19 在两种原位免疫活性的小鼠神经胶质瘤模型的肿瘤微环境中积累。此外，静脉内给予 L19-mIL12 或 L19-mTNF 可治愈一部分荷瘤小鼠，而 L19-IL2 则不能。这种治疗活性在 RAG 小鼠或耗尽 CD4 或 CD8 T 细胞时被消除，表明存在适应性免疫。从机制上讲，两种免疫细胞因子都促进了肿瘤浸润淋巴细胞，并增加了肿瘤微环境中的促炎细胞因子的含量。此外，L19-mTNF 诱导肿瘤坏死。将完全人源化的 L19-TNF 融合蛋白给予胶质母细胞瘤患者（NCT03779230）是安全的，可降低肿瘤内的区域血液灌注，并与肿瘤坏死增加和肿瘤浸润的 CD4 和 CD8 T 细胞增加相关。广泛的临床前特征和随后的临床转化为使用免疫细胞因子治疗恶性脑肿瘤的未来研究提供了有力的基础。
