Machiels J P, Reilly R T, Emens L A, Ercolini A M, Lei R Y, Weintraub D, Okoye F I, Jaffee E M
The Johns Hopkins University School of Medicine, Department of Oncology, Graduate Program in Immunology, Baltimore, Maryland 21231, USA.
Cancer Res. 2001 May 1;61(9):3689-97.
Tumor-specific immune tolerance limits the effectiveness of cancer vaccines. In addition, tumor vaccines alone have a limited potential for the treatment of measurable tumor burdens. This highlights the importance of identifying more potent cancer vaccine strategies for clinical testing. We tested immune-modulating doses of chemotherapy in combination with a granulocyte/macrophage-colony stimulating factor (GM-CSF)-secreting, HER-2/neu (neu)-expressing whole-cell vaccine as a means to treat existing mammary tumors in antigen-specific tolerized neu transgenic mice. Earlier studies have shown that neu transgenic mice exhibit immune tolerance to the neu-expressing tumors similar to what is observed in patients with cancer. We found that cyclophosphamide, paclitaxel, and doxorubicin, when given in a defined sequence with a GM-CSF-secreting, neu-expressing whole-cell vaccine, enhanced the vaccine's potential to delay tumor growth in neu transgenic mice. In addition, we showed that these drugs mediate their effects by enhancing the efficacy of the vaccine rather than via a direct cytolytic effect on cancer cells. Furthermore, paclitaxel and cyclophosphamide appear to amplify the T helper 1 neu-specific T-cell response. These findings suggest that the combined treatment with immune-modulating doses of chemotherapy and the GM-CSF-secreting neu vaccine can overcome immune tolerance and induce an antigen-specific antitumor immune response. These data provide the immunological rationale for testing immune-modulating doses of chemotherapy in combination with tumor vaccines in patients with cancer.
肿瘤特异性免疫耐受限制了癌症疫苗的有效性。此外，单独使用肿瘤疫苗治疗可测量的肿瘤负荷的潜力有限。这凸显了确定更有效的癌症疫苗策略用于临床试验的重要性。我们测试了免疫调节剂量的化疗药物与一种分泌粒细胞/巨噬细胞集落刺激因子（GM-CSF）、表达HER-2/neu（neu）的全细胞疫苗联合使用，以此作为治疗抗原特异性耐受的neu转基因小鼠中现有乳腺肿瘤的一种方法。早期研究表明，neu转基因小鼠对表达neu的肿瘤表现出免疫耐受，类似于癌症患者中观察到的情况。我们发现，环磷酰胺、紫杉醇和阿霉素在与分泌GM-CSF、表达neu的全细胞疫苗按特定顺序给药时，增强了疫苗在neu转基因小鼠中延缓肿瘤生长的潜力。此外，我们表明这些药物通过增强疫苗的效力来介导其作用，而非通过对癌细胞的直接细胞溶解作用。此外，紫杉醇和环磷酰胺似乎能增强辅助性T细胞1型neu特异性T细胞反应。这些发现表明，免疫调节剂量的化疗与分泌GM-CSF的neu疫苗联合治疗可克服免疫耐受并诱导抗原特异性抗肿瘤免疫反应。这些数据为在癌症患者中测试免疫调节剂量的化疗与肿瘤疫苗联合使用提供了免疫学依据。
