Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 92093, USA.
Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA.
Nat Commun. 2022 Jul 5;13(1):3869. doi: 10.1038/s41467-022-31601-z.
Locally advanced cancers remain therapeutically challenging to eradicate. The most successful treatments continue to combine decades old non-targeted chemotherapies with radiotherapy that unfortunately increase normal tissue damage in the irradiated field and have systemic toxicities precluding further treatment intensification. Therefore, alternative molecularly guided systemic therapies are needed to improve patient outcomes when applied with radiotherapy. In this work, we report a trimodal precision cytotoxic chemo-radio-immunotherapy paradigm using spatially targeted auristatin warheads. Tumor-directed antibodies and peptides conjugated to radiosensitizing monomethyl auristatin E (MMAE) specifically produce CD8 T cell dependent durable tumor control of irradiated tumors and immunologic memory. In combination with ionizing radiation, MMAE sculpts the tumor immune infiltrate to potentiate immune checkpoint inhibition. Here, we report therapeutic synergies of targeted cytotoxic auristatin radiosensitization to stimulate anti-tumor immune responses providing a rationale for clinical translational of auristatin antibody drug conjugates with radio-immunotherapy combinations to improve tumor control.
局部晚期癌症在治疗上仍然难以根除。最成功的治疗方法仍然是将几十年前的非靶向化疗与放疗相结合，但不幸的是，这会增加放射野内正常组织的损伤，并产生全身性毒性，从而排除了进一步的治疗强化。因此，当与放疗联合应用时，需要替代的分子指导的系统性治疗方法来改善患者的预后。在这项工作中，我们报告了一种使用空间靶向奥瑞他汀弹头的三模态精准细胞毒化疗-放疗-免疫治疗范例。肿瘤靶向抗体和肽与放射增敏单甲基奥瑞他汀 E（MMAE）缀合，可特异性产生 CD8 T 细胞依赖性持久的肿瘤控制和免疫记忆。与电离辐射结合，MMAE 可塑造肿瘤免疫浸润，增强免疫检查点抑制。在这里，我们报告了靶向细胞毒奥瑞他汀放射增敏以刺激抗肿瘤免疫反应的治疗协同作用，为临床转化奥瑞他汀抗体药物偶联物与放射免疫治疗联合应用以改善肿瘤控制提供了依据。
