免疫系統(tǒng)的反常調(diào)節(jié)和抑制作用往往會誘發(fā)癌癥的發(fā)生，很多治療策略旨在重新激活機體免疫系統(tǒng)識別癌細胞并且靶向殺滅癌細胞。

　　2016年12月13日，美國癌癥研究學會官方期刊《臨床癌癥研究》在線發(fā)表賓夕法尼亞大學、莫菲特癌癥中心的研究報告，開發(fā)出一種能夠靶向作用于乳腺癌細胞表面HER2蛋白的樹突細胞疫苗，這種新型疫苗能夠安全有效地刺激機體免疫應答，有效逆轉(zhuǎn)早期乳腺癌發(fā)生。

　　大約20%～25%的乳腺癌過度表達HER2蛋白，而且該蛋白與乳腺癌惡性程度以及患者預后較差直接相關。既往研究表明，免疫細胞并不能夠有效識別并且靶向作用于表達HER2蛋白的癌細胞，而HER2能夠作為癌癥進展到惡性侵襲階段的標志，這就表明在癌癥發(fā)生過程中，刺激機體免疫系統(tǒng)識別并且靶向作用于HER2或許是一種有效的治療策略。

　　此前，研究者開發(fā)了一種能夠幫助機體免疫系統(tǒng)識別乳腺癌細胞表面HER2蛋白的疫苗，這種方法主要包括從每位患者機體中采集樹突細胞，并利用這些樹突細胞制造個體化疫苗。為了確定這種HER2樹突細胞疫苗的安全性和有效性，首先從54例HER2陽性早期乳腺癌（42例乳腺導管原位癌，12例早期浸潤性乳腺癌）患者的血液分離樹突細胞，并將樹突細胞暴露于HER2蛋白片段中，隨后將這種個體化樹突細胞疫苗隨機注射到患者的病灶內(nèi)（19例）、淋巴結內(nèi)（19例）、病灶內(nèi)和淋巴結內(nèi)（16例），每周1次，連續(xù)注射6周。

　　結果發(fā)現(xiàn)，患者對這種樹突細胞疫苗的耐受性良好，僅有1級（68.5%）或2級（27.8%）不良反應，最常見的疫苗相關不良反應為疲倦（40.7%）、注射部位反應（40.7%）、畏寒或寒戰(zhàn)（25.9%）。

　　這種疫苗能夠有效激活絕大多數(shù)患者機體的免疫應答，注射到病灶內(nèi)、淋巴結內(nèi)、病灶內(nèi)和淋巴結內(nèi)的免疫應答率分別為84.2%、89.5%、66.7%，無顯著差異（P=0.30）。

　　乳腺導管原位癌與早期浸潤性乳腺癌相比，病理學完全緩解率較高，分別為28.6%、8.3%。

　　達到病理學完全緩解（12例）和未達到病理學完全緩解（30例）的乳腺導管原位癌患者外周血抗HER2免疫應答相似。

　　所有病理學完全緩解患者的前哨淋巴結產(chǎn)生抗HER2的CD4免疫應答，并且應答譜（P=0.03）和累積應答（P=0.04）的定量應答水平較高。

　　因此，這種新型抗HER2疫苗對乳腺導管原位癌是一種安全有效的免疫治療方法，可誘導HER2陽性患者的腫瘤特異性T細胞應答，臨床和免疫應答與接種途徑無關。然而，后期還需要在乳腺導管原位癌以及其他癌癥進行進一步檢測，局部區(qū)域前哨淋巴結（而非外周血）免疫應答可以作為反映抗腫瘤活性的較好指標。

Clin Cancer Res. 2016 Dec 13. [Epub ahead of print]

Dendritic Cell Vaccination Enhances Immune Responses and Induces Regression of HER2pos DCIS Independent of Route: Results of Randomized Selection Design Trial.

Lowenfeld L, Mick R, Datta J, Xu S, Fitzpatrick E, Fisher CS, Fox KR, DeMichele A, Zhang P, Weinstein S, Roses RE, Czerniecki BJ.

University of Pennsylvania; H. Lee Moffitt Cancer Center.

PURPOSE: Vaccination with HER2 peptide-pulsed DC1s stimulates a HER2 specific T-cell response. This randomized trial aimed to establish safety and evaluate immune and clinical responses to vaccination via intralesional (IL), intranodal (IN), or both intralesional and intranodal (ILN) injection.

METHODS: Fifty-four HER2pos patients (42 pure DCIS, 12 early invasive breast cancer (IBC)) were enrolled in a neoadjuvant HER2 peptide-pulsed DC1 vaccine trial. Patients were randomized to IL (n=19), IN (n=19), or ILN (n=16) injection. Immune responses were measured in peripheral blood and sentinel lymph nodes by ELISPOT or in-vitro sensitization assay. Pathologic response was assessed in resected surgical specimens.

RESULTS: Vaccination by all injection routes was well-tolerated. There was no significant difference in immune response rates by vaccination route (IL 84.2% vs. IN 89.5% vs. ILN 66.7%; p=0.30). The pathologic complete response (pCR) rate was higher in DCIS patients compared with IBC patients (28.6% vs. 8.3%). DCIS patients who achieved pCR (n=12) and who did not achieve pCR (n=30) had similar peripheral blood anti-HER2 immune responses. All patients who achieved pCR had an anti-HER2 CD4 immune response in the sentinel lymph node and the quantified response was higher by response repertoire (p=0.03) and cumulative response (p=0.04).

CONCLUSION: Anti-HER2 DC1 vaccination is a safe and immunogenic treatment to induce tumor-specific T-cell responses in HER2pos patients; immune and clinical responses were similar independent of vaccination route. The immune response in the sentinel lymph nodes, rather than in the peripheral blood, may serve as an endpoint more reflective of anti-tumor activity.

PMID: 27965306

PII: clincanres.1924.2016

DOI: 10.1158/1078-0432.CCR-16-1924