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。最成功的治疗方法继续将数十年历史的非靶向化疗与放疗结合起来，不幸的是，放疗增加了照射区域的正常组织损伤，并具有全身毒性，阻碍了进一步强化治疗。因此，在应用放射治疗时，需要替代的分子引导全身疗法来改善患者的治疗效果。在这项工作中，我们报告了一种使用空间靶向阿里他汀弹头的三模式精准细胞毒性化学放射免疫治疗范例。与放射增敏单甲基奥瑞他汀 E (MMAE) 缀合的肿瘤定向抗体和肽特异性产生 CD8 T 细胞依赖性的对受辐射肿瘤的持久肿瘤控制和免疫记忆。MMAE 与电离辐射相结合，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性阿里他汀放射增敏刺激抗肿瘤免疫反应的治疗协同作用，为阿里他汀抗体药物缀合物与放射免疫疗法组合的临床转化提供了理论依据，以改善肿瘤控制。