PDF(Pubmed)
Abstract：
OBJECTIVE: CpG ODN is a Toll-like receptor 9 agonist with immunotherapeutic potential for many cancer types, including aggressive breast cancers. There is strong interest in utilizing CpG ODN as an adjuvant to improve clinical efficacy of current treatments and immunogenicity of breast cancers not traditionally responsive to active immunotherapy, such as those that are human epidermal growth factor receptor 2 (HER2)-positive. This study aimed to study the efficacy and safety of combination CpG ODN plus anti-HER2 antibody trastuzumab treatment in patients with advanced/metastatic breast cancer.
METHODS: This single-arm, open-label phase II clinical trial treated patients (n = 6) with advanced/metastatic HER2-positive breast cancer with weekly subcutaneous CpG ODN and trastuzumab. Patients may have received any number of prior therapies to be enrolled (most enrolled at median 1 prior line of chemotherapy). Peripheral blood was collected at baseline and weeks 2, 6, 12, and 18 for immune analyses. Six patients were enrolled and 50% achieved stable disease (SD) response.
RESULTS: Median PFS was 8.3 months. Three of the six patients enrolled opted to stop treatment due to tolerability issues. Multiplex assay for cytokine measurements revealed significantly higher VEGF-D levels at week 2 compared to baseline. Peripheral blood mononuclear cells analyzed by flow cytometry showed a significant increase in monocytic MDSC between weeks 6 and 12. Patients with progressive disease tended to have higher levels of week 6 monocytic MDSC and PD-1+ T cells than patients with SD. NK cell populations did not significantly change throughout treatment.
CONCLUSIONS: CpG ODN and trastuzumab treatment of metastatic HER2 + breast cancer was safe but was not tolerable for all patients. This combination did induce potentially predictive immune profile changes in treated patients with metastatic HER2 + breast cancer, the significance of which needs to be further explored.
Why was the study done? Breast cancer that has metastasized (moved outside of the breast and local lymph nodes) is currently considered incurable and can be difficult to treat. Treatments that can stimulate the immune system to recognize cancer cells have been found to be useful for many types of cancers, including some types of breast cancers. This study tested a new immune stimulator (CpG ODN) in combination with a currently on-the-market antibody treatment for breast cancer (trastuzumab). What did the researchers do? The research team enrolled patients who had metastatic breast cancer and treated them all with a combination of trastuzumab and CpG ODN for 12 weeks. These patients were monitored for any side effects/toxicity, monitored for how long their breast cancer responded to this treatment, and monitored for how long they lived after beginning this treatment. Patients also had their blood drawn at different time points to observe how their immune cells and immune proteins (e.g. cytokines) changed on treatment. What did the researchers find? The research team enrolled six patients and found that the treatment was safe and that 50% of the patients treated did not have any breast cancer growth when given CpG ODN plus trastuzumab. Looking at the immune cells in the patient blood samples, some cells that are known to decrease the immune response to cancers (myeloid-derived suppressor cells) did increase towards the end of treatment. What do the findings mean? Overall, CpG ODN and trastuzumab treatment was found to be safe and potentially effective in preventing breast cancer growth.
METHODS: This single-arm, open-label phase II clinical trial treated patients (n = 6) with advanced/metastatic HER2-positive breast cancer with weekly subcutaneous CpG ODN and trastuzumab. Patients may have received any number of prior therapies to be enrolled (most enrolled at median 1 prior line of chemotherapy). Peripheral blood was collected at baseline and weeks 2, 6, 12, and 18 for immune analyses. Six patients were enrolled and 50% achieved stable disease (SD) response.
RESULTS: Median PFS was 8.3 months. Three of the six patients enrolled opted to stop treatment due to tolerability issues. Multiplex assay for cytokine measurements revealed significantly higher VEGF-D levels at week 2 compared to baseline. Peripheral blood mononuclear cells analyzed by flow cytometry showed a significant increase in monocytic MDSC between weeks 6 and 12. Patients with progressive disease tended to have higher levels of week 6 monocytic MDSC and PD-1+ T cells than patients with SD. NK cell populations did not significantly change throughout treatment.
CONCLUSIONS: CpG ODN and trastuzumab treatment of metastatic HER2 + breast cancer was safe but was not tolerable for all patients. This combination did induce potentially predictive immune profile changes in treated patients with metastatic HER2 + breast cancer, the significance of which needs to be further explored.
Why was the study done? Breast cancer that has metastasized (moved outside of the breast and local lymph nodes) is currently considered incurable and can be difficult to treat. Treatments that can stimulate the immune system to recognize cancer cells have been found to be useful for many types of cancers, including some types of breast cancers. This study tested a new immune stimulator (CpG ODN) in combination with a currently on-the-market antibody treatment for breast cancer (trastuzumab). What did the researchers do? The research team enrolled patients who had metastatic breast cancer and treated them all with a combination of trastuzumab and CpG ODN for 12 weeks. These patients were monitored for any side effects/toxicity, monitored for how long their breast cancer responded to this treatment, and monitored for how long they lived after beginning this treatment. Patients also had their blood drawn at different time points to observe how their immune cells and immune proteins (e.g. cytokines) changed on treatment. What did the researchers find? The research team enrolled six patients and found that the treatment was safe and that 50% of the patients treated did not have any breast cancer growth when given CpG ODN plus trastuzumab. Looking at the immune cells in the patient blood samples, some cells that are known to decrease the immune response to cancers (myeloid-derived suppressor cells) did increase towards the end of treatment. What do the findings mean? Overall, CpG ODN and trastuzumab treatment was found to be safe and potentially effective in preventing breast cancer growth.
摘要：
目的：CpGODN是一种Toll样受体9激动剂，对许多癌症类型具有免疫治疗潜力，包括侵袭性乳腺癌.人们对利用CpGODN作为佐剂来提高当前治疗的临床疗效和传统上对主动免疫疗法无反应的乳腺癌的免疫原性有强烈的兴趣。例如人类表皮生长因子受体2（HER2）阳性。本研究旨在研究CpGODN联合抗HER2抗体曲妥珠单抗治疗晚期/转移性乳腺癌患者的疗效和安全性。
方法：这种单臂，开放标签II期临床试验每周皮下CpGODN和曲妥珠单抗治疗晚期/转移性HER2阳性乳腺癌患者(n=6).患者可能已经接受了任何数量的先前疗法来登记(大多数登记在中位1个先前的化疗线)。在基线和第2、6、12和18周收集外周血用于免疫分析。入组6名患者，50％达到稳定的疾病（SD）反应。
结果：PFS中位数为8.3个月。由于耐受性问题，六名患者中有三名选择停止治疗。细胞因子测量的多重分析显示，与基线相比，第2周的VEGF-D水平明显更高。通过流式细胞术分析的外周血单核细胞显示在第6周和第12周之间单核细胞MDSC显著增加。患有进行性疾病的患者倾向于比患有SD的患者具有更高水平的第6周单核细胞MDSC和PD-1+T细胞。NK细胞群体在整个治疗中没有显著变化。
结论：CpGODN和曲妥珠单抗治疗转移性HER2+乳腺癌是安全的，但并非所有患者都能耐受。这种组合确实在转移性HER2+乳腺癌治疗患者中诱导了潜在的预测免疫谱变化，其意义有待进一步探讨。
为什么要做这项研究？已经转移（转移到乳腺和局部淋巴结之外）的乳腺癌目前被认为是无法治愈的，并且可能难以治疗。已经发现可以刺激免疫系统识别癌细胞的治疗对许多类型的癌症都是有用的。包括某些类型的乳腺癌。这项研究测试了一种新的免疫刺激剂（CpGODN）与目前上市的乳腺癌抗体治疗（曲妥珠单抗）的组合。研究人员做了什么？研究小组招募了患有转移性乳腺癌的患者，并用曲妥珠单抗和CpGODN联合治疗他们12周。监测这些患者的任何副作用/毒性，监测他们的乳腺癌对这种治疗有多长时间的反应，并监测他们在开始治疗后的寿命。患者还在不同的时间点抽血以观察他们的免疫细胞和免疫蛋白(例如细胞因子)在治疗时如何变化。研究人员发现了什么？研究小组招募了6名患者，发现治疗是安全的，当给予CpGODN加曲妥珠单抗时，50％的患者没有任何乳腺癌生长。观察患者血液样本中的免疫细胞，一些已知会降低对癌症的免疫反应的细胞(骨髓来源的抑制细胞)在治疗结束时确实增加了.这些发现意味着什么？总的来说，发现CpGODN和曲妥珠单抗治疗在预防乳腺癌生长方面是安全且潜在有效的。
方法：这种单臂，开放标签II期临床试验每周皮下CpGODN和曲妥珠单抗治疗晚期/转移性HER2阳性乳腺癌患者(n=6).患者可能已经接受了任何数量的先前疗法来登记(大多数登记在中位1个先前的化疗线)。在基线和第2、6、12和18周收集外周血用于免疫分析。入组6名患者，50％达到稳定的疾病（SD）反应。
结果：PFS中位数为8.3个月。由于耐受性问题，六名患者中有三名选择停止治疗。细胞因子测量的多重分析显示，与基线相比，第2周的VEGF-D水平明显更高。通过流式细胞术分析的外周血单核细胞显示在第6周和第12周之间单核细胞MDSC显著增加。患有进行性疾病的患者倾向于比患有SD的患者具有更高水平的第6周单核细胞MDSC和PD-1+T细胞。NK细胞群体在整个治疗中没有显著变化。
结论：CpGODN和曲妥珠单抗治疗转移性HER2+乳腺癌是安全的，但并非所有患者都能耐受。这种组合确实在转移性HER2+乳腺癌治疗患者中诱导了潜在的预测免疫谱变化，其意义有待进一步探讨。
为什么要做这项研究？已经转移（转移到乳腺和局部淋巴结之外）的乳腺癌目前被认为是无法治愈的，并且可能难以治疗。已经发现可以刺激免疫系统识别癌细胞的治疗对许多类型的癌症都是有用的。包括某些类型的乳腺癌。这项研究测试了一种新的免疫刺激剂（CpGODN）与目前上市的乳腺癌抗体治疗（曲妥珠单抗）的组合。研究人员做了什么？研究小组招募了患有转移性乳腺癌的患者，并用曲妥珠单抗和CpGODN联合治疗他们12周。监测这些患者的任何副作用/毒性，监测他们的乳腺癌对这种治疗有多长时间的反应，并监测他们在开始治疗后的寿命。患者还在不同的时间点抽血以观察他们的免疫细胞和免疫蛋白(例如细胞因子)在治疗时如何变化。研究人员发现了什么？研究小组招募了6名患者，发现治疗是安全的，当给予CpGODN加曲妥珠单抗时，50％的患者没有任何乳腺癌生长。观察患者血液样本中的免疫细胞，一些已知会降低对癌症的免疫反应的细胞(骨髓来源的抑制细胞)在治疗结束时确实增加了.这些发现意味着什么？总的来说，发现CpGODN和曲妥珠单抗治疗在预防乳腺癌生长方面是安全且潜在有效的。
