表皮生长因子受体靶向免疫疗法与光动力疗法对卵巢癌的体内协同作用。

Synergism of epidermal growth factor receptor-targeted immunotherapy with photodynamic treatment of ovarian cancer in vivo.

作者信息

del Carmen Marcela G, Rizvi Imran, Chang Yuchiao, Moor Anne C E, Oliva Esther, Sherwood Margaret, Pogue Brian, Hasan Tayyaba

机构信息

Wellman Center for Photomedicine, Department of Dermatology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.

出版信息

J Natl Cancer Inst. 2005 Oct 19;97(20):1516-24. doi: 10.1093/jnci/dji314.

DOI:10.1093/jnci/dji314

PMID:16234565

Abstract

BACKGROUND

Epithelial ovarian cancer often develops resistance to standard treatments, which is a major reason for the high mortality associated with the disease. We examined the efficacy of a treatment regimen that combines immunotherapy to block the activity of epidermal growth factor receptor (EGFR), overexpression of which is associated with the development of resistant ovarian cancer, and photodynamic therapy (PDT), a mechanistically distinct photochemistry-based modality that is effective against chemo- and radioresistant ovarian tumors.

METHODS

We tested a combination regimen consisting of C225, a monoclonal antibody that inhibits the receptor tyrosine kinase activity of EGFR, and benzoporphyrin derivative monoacid A (BPD)-based PDT in a mouse model of human ovarian cancer. Therapeutic efficacy was evaluated in acute treatment response and survival studies that used 9-19 mice per group. Analysis of variance and Wilcoxon statistics were used to analyze the data. All statistical tests were two-sided.

RESULTS

Mice treated with PDT + C225 had the lowest mean tumor burden compared with that in the no-treatment control mice (mean percent tumor burden = 9.8%, 95% confidence interval [CI] = 2.3% to 17.3%, P < .001). Mean percent tumor burden for mice treated with C225 only or PDT only was 66.6% (95% CI = 58.7% to 74.4%, P < .001) and 38.2% (95% CI = 29.3% to 47.0%, P < .001), respectively. When compared with PDT only or C225 only, PDT + C225 produced synergistic reductions in mean tumor burden (P < .001, analysis of variance) and improvements in survival (P = .0269, Wilcoxon test). Median survival was approximately threefold greater for mice in the PDT + C225 group than for mice in the no-treatment control group (80 days versus 28 days), and more mice in the PDT + C225 group were alive at 180 days (3/9; 33% [95% CI = 7% to 70%]) than mice in the C225-only (0/12; 0% [95% CI = 0% to 22%]) or PDT-only (1/10; 10% [95% CI = 0.2% to 44%]) groups.

CONCLUSION

A mechanistically nonoverlapping combination modality consisting of receptor tyrosine kinase inhibition with C225 and BPD-PDT is well tolerated, effective, and synergistic in mice.

摘要

背景

上皮性卵巢癌常对标准治疗产生耐药性，这是该疾病死亡率高的主要原因。我们研究了一种联合治疗方案的疗效，该方案将阻断表皮生长因子受体（EGFR）活性的免疫疗法与光动力疗法（PDT）相结合，EGFR的过表达与耐药性卵巢癌的发生相关，而光动力疗法是一种基于光化学的、作用机制不同的治疗方法，对化疗和放疗耐药的卵巢肿瘤有效。

方法

我们在人卵巢癌小鼠模型中测试了一种联合治疗方案，该方案由抑制EGFR受体酪氨酸激酶活性的单克隆抗体C225和基于苯并卟啉衍生物单酸A（BPD）的光动力疗法组成。在急性治疗反应和生存研究中评估治疗效果，每组使用9 - 19只小鼠。采用方差分析和威尔科克森统计分析数据。所有统计检验均为双侧检验。

结果

与未治疗的对照小鼠相比，接受光动力疗法 + C225治疗的小鼠平均肿瘤负荷最低（平均肿瘤负荷百分比 = 9.8%，95%置信区间[CI] = 2.3%至17.3%，P <.001）。仅接受C225或仅接受光动力疗法治疗的小鼠平均肿瘤负荷百分比分别为66.6%（95%CI = 58.7%至74.4%，P <.001）和38.2%（95%CI = 29.3%至47.0%，P <.001）。与仅接受光动力疗法或仅接受C225相比，光动力疗法 + C225联合治疗使平均肿瘤负荷产生协同降低（P <.001，方差分析），并改善了生存情况（P =.0269，威尔科克森检验）。光动力疗法 + C225组小鼠的中位生存期比未治疗对照组小鼠长约三倍（80天对28天），并且在180天时，光动力疗法 + C225组存活的小鼠（3/9；33%[95%CI = 7%至70%]）比仅接受C225组（0/12；0%[95%CI = 0%至22%]）或仅接受光动力疗法组（1/10；10%[95%CI = 0.2%至44%]）的小鼠多。