Timed Sequential Treatment With Cyclophosphamide, Doxorubicin, and an Allogeneic Granulocyte-Macrophage Colony-Stimulating Factor-Secreting Breast Tumor Vaccine: A Chemotherapy Dose-Ranging Factorial Study of Safety and Immune Activation
Timed Sequential Treatment With Cyclophosphamide, Doxorubicin, and an Allogeneic Granulocyte-Macrophage Colony-Stimulating Factor-Secreting Breast Tumor Vaccine: A Chemotherapy Dose-Ranging Factorial Study of Safety and Immune Activation
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DOI：
10.1200/jco.2009.23.3494
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发表时间：
2009-12-10
影响因子：
45.3
通讯作者：
Jaffee, Elizabeth M.
中科院分区：
文献类型：
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作者：
Emens, Leisha A.;Asquith, Justin M.;Jaffee, Elizabeth M.
目的粒细胞-巨噬细胞集落刺激因子（GM-CSF）肿瘤疫苗已显示出生物活性，但可能受到疾病负荷和免疫耐受的限制。我们测试的假设，环磷酰胺（CY）和阿霉素（DOX）可以提高疫苗诱导的免疫力，在乳腺癌患者。患者和MethodsWe进行了3 × 3析因（响应面）剂量范围的研究CY，DOX，和HER 2阳性，同种异体，GM-CSF分泌肿瘤疫苗在28例转移性乳腺癌。患者每月接受三次免疫接种，从研究开始后6至8个月进行加强。主要目标包括安全性和确定的化疗剂量，最大限度地提高HER 2特异性immunity.ResultsTwenty-eight患者至少接受了一次免疫接种，16例患者接受了四次免疫接种。未观察到剂量限制性毒性。大多数单独接种疫苗或与200 mg/m2环磷酰胺联合接种的患者发生HER 2特异性迟发型超敏反应。200 mg/m2 CY和35 mg/m2 DOX可增强HER 2特异性抗体应答，但更高剂量的CY可抑制免疫。分析显示，CY在200 mg/m2和DOX在35 mg/m2的组合，产生最高的抗体responses.ConclusionFirst，免疫治疗与同种异体，HER 2阳性，GM-CSF分泌乳腺肿瘤疫苗单独或与CY和DOX是安全的，并诱导转移性乳腺癌患者的HER 2特异性免疫。其次，低剂量CY的免疫调节活性具有狭窄的治疗窗口，最佳剂量不超过200 mg/m2。第三，析因设计提供了一个机会，以确定最积极的相互作用的药物组合的患者。进一步研究化疗对疫苗诱导免疫的影响是必要的。
PurposeGranulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccines have demonstrated bioactivity but may be limited by disease burdens and immune tolerance. We tested the hypothesis that cyclophosphamide (CY) and doxorubicin (DOX) can enhance vaccine-induced immunity in patients with breast cancer.Patients and MethodsWe conducted a 3 x 3 factorial (response surface) dose-ranging study of CY, DOX, and an HER2-positive, allogeneic, GM-CSF-secreting tumor vaccine in 28 patients with metastatic breast cancer. Patients received three monthly immunizations, with a boost 6 to 8 months from study entry. Primary objectives included safety and determination of the chemotherapy doses that maximize HER2-specific immunity.ResultsTwenty-eight patients received at least one immunization, and 16 patients received four immunizations. No dose-limiting toxicities were observed. HER2-specific delayed-type hypersensitivity developed in most patients who received vaccine alone or with 200 mg/m(2) CY. HER2-specific antibody responses were enhanced by 200 mg/m(2) CY and 35 mg/m(2) DOX, but higher CY doses suppressed immunity. Analyses revealed that CY at 200 mg/m(2) and DOX at 35 mg/m(2) is the combination that produced the highest antibody responses.ConclusionFirst, immunotherapy with an allogeneic, HER2-positive, GM-CSF-secreting breast tumor vaccine alone or with CY and DOX is safe and induces HER2-specific immunity in patients with metastatic breast cancer. Second, the immunomodulatory activity of low-dose CY has a narrow therapeutic window, with an optimal dose not exceeding 200 mg/m(2). Third, factorial designs provide an opportunity to identify the most active combination of interacting drugs in patients. Further investigation of the impact of chemotherapy on vaccine-induced immunity is warranted.