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免疫系统的反常调节和抑制作用往往会诱发癌症的发生，很多治疗策略旨在重新激活机体免疫系统识别癌细胞并且靶向杀灭癌细胞。 2016年12月13日，美国癌症研究学会官方期刊《临床癌症研究》在线发表宾夕法尼亚大学、莫菲特癌症中心的研究报告，开发出一种能够靶向作用于乳腺癌细胞表面HER2蛋白的树突细胞疫苗，这种新型疫苗能够安全有效地刺激机体免疫应答，有效逆转早期乳腺癌发生。 大约20%～25%的乳腺癌过度表达HER2蛋白，而且该蛋白与乳腺癌恶性程度以及患者预后较差直接相关。既往研究表明，免疫细胞并不能够有效识别并且靶向作用于表达HER2蛋白的癌细胞，而HER2能够作为癌症进展到恶性侵袭阶段的标志，这就表明在癌症发生过程中，刺激机体免疫系统识别并且靶向作用于HER2或许是一种有效的治疗策略。 此前，研究者开发了一种能够帮助机体免疫系统识别乳腺癌细胞表面HER2蛋白的疫苗，这种方法主要包括从每位患者机体中采集树突细胞，并利用这些树突细胞制造个体化疫苗。为了确定这种HER2树突细胞疫苗的安全性和有效性，首先从54例HER2阳性早期乳腺癌（42例乳腺导管原位癌，12例早期浸润性乳腺癌）患者的血液分离树突细胞，并将树突细胞暴露于HER2蛋白片段中，随后将这种个体化树突细胞疫苗随机注射到患者的病灶内（19例）、淋巴结内（19例）、病灶内和淋巴结内（16例），每周1次，连续注射6周。 结果发现，患者对这种树突细胞疫苗的耐受性良好，仅有1级（68.5%）或2级（27.8%）不良反应，最常见的疫苗相关不良反应为疲倦（40.7%）、注射部位反应（40.7%）、畏寒或寒战（25.9%）。 这种疫苗能够有效激活绝大多数患者机体的免疫应答，注射到病灶内、淋巴结内、病灶内和淋巴结内的免疫应答率分别为84.2%、89.5%、66.7%，无显著差异（P=0.30）。 乳腺导管原位癌与早期浸润性乳腺癌相比，病理学完全缓解率较高，分别为28.6%、8.3%。 达到病理学完全缓解（12例）和未达到病理学完全缓解（30例）的乳腺导管原位癌患者外周血抗HER2免疫应答相似。 所有病理学完全缓解患者的前哨淋巴结产生抗HER2的CD4免疫应答，并且应答谱（P=0.03）和累积应答（P=0.04）的定量应答水平较高。 因此，这种新型抗HER2疫苗对乳腺导管原位癌是一种安全有效的免疫治疗方法，可诱导HER2阳性患者的肿瘤特异性T细胞应答，临床和免疫应答与接种途径无关。然而，后期还需要在乳腺导管原位癌以及其他癌症进行进一步检测，局部区域前哨淋巴结（而非外周血）免疫应答可以作为反映抗肿瘤活性的较好指标。 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
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