Bandara N Achini, Bates Cody D, Lu Yingjuan, Hoylman Emily K, Low Philip S
Department of Chemistry, Purdue University, West Lafayette, Indiana.
Endocyte, Inc., West Lafayette, Indiana.
Mol Cancer Ther. 2017 Mar;16(3):461-468. doi: 10.1158/1535-7163.MCT-16-0569. Epub 2016 Dec 15.
The overexpression of folate receptors (FR) on many human cancers has led to the development of folate-linked drugs for the imaging and therapy of FR-expressing cancers. In a recent phase I clinical trial of late-stage renal cell carcinoma patients, folate was exploited to deliver an immunogenic hapten, fluorescein, to FR tumor cells in an effort to render the cancer cells more immunogenic. Although >50% of the patients showed prolonged stable disease, all patients eventually progressed, suggesting that the folate-hapten immunotherapy was insufficient by itself to treat the cancer. In an effort to identify a companion therapy that might augment the folate-hapten immunotherapy, we explored coadministration of two approved cancer drugs that had been previously shown to also stimulate the immune system. We report that sunitinib and axitinib (VEGF receptor inhibitors that simultaneously mitigate immune suppression) synergize with the folate-hapten-targeted immunotherapy to reduce tumor growth in three different syngeneic murine tumor models. We further demonstrate that the combination therapy not only enhances tumor infiltration of CD4 and CD8 effector cells, but surprisingly reduces tumor neovasculogenesis more than predicted. Subsequent investigation of the mechanism for this unexpected suppression of neovasculogenesis revealed that it is independent of elimination of any tumor cells, but instead likely derives from a reduction in the numbers of FR tumor-associated macrophages and myeloid-derived suppressor cells, that is, immunosuppressive cells that release significant quantities of VEGF. These data suggest that a reduction in stromal cells of myeloid origin can inhibit tumor growth by suppressing neovasculogenesis. .
叶酸受体（FR）在许多人类癌症上的过表达促使了用于对表达FR的癌症进行成像和治疗的叶酸连接药物的开发。在最近一项针对晚期肾细胞癌患者的I期临床试验中，利用叶酸将免疫原性半抗原荧光素递送至FR肿瘤细胞，以使癌细胞更具免疫原性。尽管超过50%的患者显示疾病稳定期延长，但所有患者最终都病情进展，这表明叶酸-半抗原免疫疗法本身不足以治疗癌症。为了确定一种可能增强叶酸-半抗原免疫疗法的辅助疗法，我们探索了联合使用两种先前已证明也能刺激免疫系统的获批癌症药物。我们报告，舒尼替尼和阿昔替尼（同时减轻免疫抑制的VEGF受体抑制剂）与叶酸-半抗原靶向免疫疗法协同作用，以减少三种不同的同基因小鼠肿瘤模型中的肿瘤生长。我们进一步证明，联合疗法不仅增强了CD4和CD8效应细胞的肿瘤浸润，而且令人惊讶地比预期更能减少肿瘤新生血管形成。随后对这种意外的新生血管形成抑制机制的研究表明，它与消除任何肿瘤细胞无关，而是可能源于FR肿瘤相关巨噬细胞和髓系来源抑制细胞数量的减少，即释放大量VEGF的免疫抑制细胞。这些数据表明，髓系来源的基质细胞减少可通过抑制新生血管形成来抑制肿瘤生长。
