Draganov Dobrin, Han Zhen, Rana Aamir, Bennett Nitasha, Irvine Darrell J, Lee Peter P
Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
Koch Institute for Integrative Cancer Research and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
NPJ Breast Cancer. 2021 Mar 2;7(1):22. doi: 10.1038/s41523-021-00229-5.
We show that treatment with the FDA-approved anti-parasitic drug ivermectin induces immunogenic cancer cell death (ICD) and robust T cell infiltration into breast tumors. As an allosteric modulator of the ATP/P2X4/P2X7 axis which operates in both cancer and immune cells, ivermectin also selectively targets immunosuppressive populations including myeloid cells and Tregs, resulting in enhanced Teff/Tregs ratio. While neither agent alone showed efficacy in vivo, combination therapy with ivermectin and checkpoint inhibitor anti-PD1 antibody achieved synergy in limiting tumor growth (p = 0.03) and promoted complete responses (p < 0.01), also leading to immunity against contralateral re-challenge with demonstrated anti-tumor immune responses. Going beyond primary tumors, this combination achieved significant reduction in relapse after neoadjuvant (p = 0.03) and adjuvant treatment (p < 0.001), and potential cures in metastatic disease (p < 0.001). Statistical modeling confirmed bona fide synergistic activity in both the adjuvant (p = 0.007) and metastatic settings (p < 0.001). Ivermectin has dual immunomodulatory and ICD-inducing effects in breast cancer, converting cold tumors hot, thus represents a rational mechanistic partner with checkpoint blockade.
我们发现，经美国食品药品监督管理局（FDA）批准的抗寄生虫药物伊维菌素治疗可诱导免疫原性癌细胞死亡（ICD），并促使强大的T细胞浸润到乳腺肿瘤中。作为一种在癌细胞和免疫细胞中均起作用的ATP/P2X4/P2X7轴变构调节剂，伊维菌素还选择性地靶向包括髓样细胞和调节性T细胞（Tregs）在内的免疫抑制群体，从而提高效应性T细胞（Teff）与Tregs的比例。虽然单独使用这两种药物在体内均未显示出疗效，但伊维菌素与检查点抑制剂抗PD1抗体联合治疗在限制肿瘤生长方面实现了协同作用（p = 0.03），并促进了完全缓解（p < 0.01），还引发了针对对侧再次攻击的免疫反应，表现出抗肿瘤免疫反应。除原发性肿瘤外，这种联合治疗在新辅助治疗（p = 0.03）和辅助治疗后（p < 0.001）显著降低了复发率，并在转移性疾病中实现了潜在治愈（p < 0.001）。统计模型证实，在辅助治疗（p = 0.007）和转移情况下（p < 0.001）均存在真正的协同活性。伊维菌素在乳腺癌中具有双重免疫调节和诱导ICD的作用，可将冷肿瘤转变为热肿瘤，因此是与检查点阻断合理的机制性搭档。
