2017年1月19日，《美国医学会杂志肿瘤学分册》在线发表华盛顿大学、免疫设计、希望之城、斯坦福大学的Ⅱ期单组临床研究报告，发现全身化疗＋局部外用免疫药物治疗乳腺癌皮肤转移安全有效。
对于乳腺癌复发性胸壁病变，解救化疗的缓解率仅为20%～30%。临床前研究表明，局部外用Toll样受体-7激动剂（咪喹莫特）可以诱导小鼠胸壁乳腺癌病变显著缩小。
Toll最初由1995年诺贝尔奖得主、德国发育遗传学家克里斯汀·纽斯林-沃尔哈德及其同事于1985年在黑腹果蝇体内发现，Toll的名称来源于她在当时的感叹：真是令人惊叹（Das ist ja toll）！意指果蝇幼虫不发达的腹部。形容词“toll”在德语中是“令人惊讶”或“伟大、棒极了”的意思。Toll最初被认为是一种对胚胎发育中的背-腹轴建立过程很重要的基因，1996年被发现会在苍蝇对真菌感染的免疫过程中发挥作用，哺乳动物和无脊椎动物的Toll基因都为先天免疫系统所必需。1997年，耶鲁大学学者确认哺乳动物的Toll样受体。在同一时期，日本、美国的两项不同研究发现Toll样受体在哺乳动物体内对感染是主感受器。由于肿瘤在发生发展过程中可以产生一些能被Toll样受体识别的内源性配体，所以Toll样受体在肿瘤免疫监视中可能发挥了一定作用。
咪喹莫特是一种人工合成的小分子免疫调节剂，可激活Toll样受体-7，具有激活天然免疫和特异性免疫、诱导肿瘤细胞自噬和凋亡、抑制肿瘤血管的形成等作用。咪喹莫特在皮肤科主要用于治疗成人外生殖器、肛周尖锐湿疣、基底细胞癌、鳞状细胞癌、皮肤转移性黑色素瘤、外阴上皮内瘤变。咪喹莫特不具有直接抗病毒活性，也不引起直接的、非特异的细胞溶解破坏作用。临床前研究提示咪喹莫特能够在用药局部诱生多种细胞因子及相关产物，从而产生免疫调节和间接抗病毒作用。咪喹莫特能够诱导人外周血单核细胞生成下列多种细胞因子：α-干扰素（IFN-α）、α-肿瘤坏死因子（TNF-α）、白细胞介素（IL-1α、IL-1β、IL-6、8、10）、集落刺激因子（C-CSF、GM-CSF）、趋化性细胞因子（MCP-1α、MCP-1β）等。咪喹莫特的美国3M原研商品名：艾达乐，国内商品名：联邦艾德欣、忧必青、扬子江天锐、明欣利迪、科益丽科杰、天方南博、华润顺峰。
本研究在15位曾于2009～2012年接受复发性胸壁病变治疗的乳腺癌患者中，评价了局部外用咪喹莫特＋全身化疗（纳米白蛋白结合型紫杉醇）治疗难治性胸壁乳腺癌的安全性和有效性。
咪喹莫特用法：每28天周期的第1～4、8～11、15～18、22～25天，连续4天、每天1次局部外用5%咪喹莫特乳膏5mg于病变部位，共12周（3个周期）。纳米白蛋白结合型紫杉醇用法：每28天周期的第1、8、15天静脉注射100mg/m²，共12周（3个周期）。
主要观察终点为安全性和客观缓解（完全缓解＋部分缓解）率，次要观察终点包括肿瘤浸润性淋巴细胞的生成和免疫细胞群的调节。
15位研究参与者入组时的中位年龄为54岁（范围：46～92岁），最终14位患者可评价。结果发现：
安全性：联合疗法与轻度毒性作用有相关性，在358例不良事件中，330例（92%）为1级和2级。
有效性：在最终可评价疗效的14位患者中，3位疾病稳定、1位疾病进展，5位（36%）完全缓解（其中4位病理学完全缓解），另5位（36%）部分缓解（其中1位病理学完全缓解），总缓解率为72%。缓解与肿瘤大小无关。缓解持续时间有限，完全缓解者、部分缓解者、疾病稳定者的治疗后中位缓解时间分别为12、16、3周（范围分别为：4～25、4～28、1～4周）。
预测性：治疗前的外周血程序性死亡蛋白-1（PD-1）阳性T细胞、单核细胞骨髓来源抑制细胞（mMDSC）水平高可以预测临床疗效次优（PD-1阳性分化簇[CD]4阳性的95%置信区间：2.68～6.63，P＜0.001；PD-1阳性CD8阳性的95%置信区间：1.13～8.35，P=0.01；mMDSC的95%置信区间：3.62～12.74，P=0.001）。
因此，使用Toll样受体-7激动剂和纳米白蛋白结合型紫杉醇进行化学免疫调节，对于诱导难治性乳腺癌胸壁转移病变消退是有效的，但是缓解短暂。治疗前提示T细胞衰竭或全身免疫抑制的细胞水平高，可能是选择有效患者的指标。
总之，即使对于难治性疾病，化疗免疫疗法也可诱导缓解，并可根据外周血生物指标预测疗效。
JAMA Oncol. 2017 Jan 19. [Epub ahead of print]
Topical Imiquimod Plus Nab-paclitaxel for Breast Cancer Cutaneous Metastases: A Phase 2 Clinical Trial.
Lupe G. Salazar; Hailing Lu; Jessica L. Reichow; Jennifer S. Childs; Andrew L. Coveler; Doreen M. Higgins; James Waisman; Kimberly H. Allison; Yushe Dang; Mary L. Disis.
University of Washington, Seattle, Washington; Immune Design, Seattle, Washington; City of Hope, Durante, California; Stanford University, Stanford, California.
This phase 2, single-arm clinical trial examines the safety and objective response rate of topical imiquimod in combination with systemic chemotherapy for treatment of breast cancer cutaneous metastases.
QUESTION: Can breast cancer of the chest wall be treated with chemoimmunotherapy?
FINDINGS: In a single-arm phase 2 clinical trial of 14 patients, 5 achieved a compete response and 5 were partial responders for an overall response rate of 72%. Elevated pretreatment levels of peripheral blood programmed death-1–positive T cells and monocytic myeloid derived suppressor cells were associated with suboptimal response.
MEANING: Even in treatment-refractory disease, chemoimmunotherapy can induce remission. Peripheral blood biomarkers associated with response can be identified.
IMPORTANCE: Salvage chemotherapy for recurrent chest wall lesions in breast cancer results in response rates of 20% to 30%. Preclinical studies showed significant disease regression could be induced in murine chest wall mammary cancers with a topical toll-like receptor (TLR)-7 agonist, imiquimod.
OBJECTIVE: To evaluate the safety and objective response rate (ORR) of imiquimod in combination with systemic albumin bound paclitaxel in treatment-refractory breast cancer of the chest wall.
DESIGN, SETTING, AND PARTICPANTS: A single arm phase 2 clinical trial of 15 patients with breast cancer previously treated in an academic medical center setting between 2009 and 2012 for chest wall disease that had recurred.
INTERVENTIONS: Imiquimod cream, 5%, was applied topically to a designated target lesion once per day for 4 consecutive days on days 1 through 4, 8 through 11, 15 through 18, and 22 through 25 of a 28-day cycle, for 12 weeks. Albumin bound paclitaxel, 100 mg/m2, was given intravenously on days 1, 8, and 15, and repeated every 28 days over the 12-week period.
MAIN OUTCOMES AND MEASURES: The primary endpoint was safety and ORR. Secondary endpoints included the generation of tumor-infiltrating lymphocytes and modulation of immune cell populations.
RESULTS: The median age at baseline of the 15 study participants was 54 years (range, 46-92 years). Fourteen patients were evaluable. Combination therapy was associated with low-grade toxic effects. Of 358 adverse events 330 (92%) were grades 1 and 2. Five (36%) patients achieved a compete response and another 5 (36%) were partial responders for an overall response rate of 72% (10 of 14). The response duration was limited. Pretreatment levels of programmed death-1 (PD-1)+ peripheral blood T cells (PD-1+ cluster of differentiation [CD]4+; 95% CI, 2.68-6.63; P < .001 and PD-1+CD8+; 95% CI, 1.13-8.35; P = .01) and monocytic myeloid derived suppressor cells (mMDSC) (95% CI, 3.62-12.74; P = .001) greater than controls predicted suboptimal clinical response.
CONCLUSIONS AND RELEVANCE: Chemoimmunomodulation with a TLR-7 agonist and albumin bound paclitaxel is effective in inducing disease regression in treatment-refractory breast cancer chest wall metastases but responses are short-lived. Preexisting levels of cells indicating either T-cell exhaustion or systemic immunosuppression may be markers of selection for responsive patients.
TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00821964
DOI: 10.1001/jamaoncol.2016.6007
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