通过靶向树突状细胞的慢病毒载体递送的乳腺癌疫苗可诱导有效的抗肿瘤免疫反应,并保护小鼠免受乳腺肿瘤生长的影响。

Breast cancer vaccines delivered by dendritic cell-targeted lentivectors induce potent antitumor immune responses and protect mice from mammary tumor growth.

作者信息

Bryson Paul D, Han Xiaolu, Truong Norman, Wang Pin

机构信息

Mork Family Department of Chemical Engineering and Materials Science, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA.

Genetic, Molecular & Cellular Biology Program, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.

出版信息

Vaccine. 2017 Oct 13;35(43):5842-5849. doi: 10.1016/j.vaccine.2017.09.017. Epub 2017 Sep 12.

Abstract

Breast cancer immunotherapy is a potent treatment option, with antibody therapies such as trastuzumab increasing 2-year survival rates by 50%. However, active immunotherapy through vaccination has generally been clinically ineffective. One potential means of improving vaccine therapy is by delivering breast cancer antigens to dendritic cells (DCs) for enhanced antigen presentation. To accomplish this in vivo, we pseudotyped lentiviral vector (LV) vaccines with a modified Sindbis Virus glycoprotein so that they could deliver genes encoding the breast cancer antigen alpha-lactalbumin (Lalba) or erb-b2 receptor tyrosine kinase 2 (ERBB2 or HER2) directly to resident DCs. We hypothesized that utilizing these DC-targeting lentiviral vectors asa breast cancer vaccine could lead to an improved immune response against self-antigens found in breast cancer tumors. Indeed, single injections of the vaccine vectors were able to amplify antigen-specific CD8T cells 4-6-fold over naïve mice, similar to the best published vaccine regimens. Immunization of these mice completely inhibited tumor growth in a foreign antigen environment (LV-ERBB2 in wildtype mice), and it reduced the rate of tumor growth in a self-antigen environment (LV-Lalba in wildtype or LV-ERBB2 in MMTV-huHER2 transgenic). These results show that a single injection with targeted lentiviral vectors can be an effective immunotherapy for breast cancer. Furthermore, they could be combined with other immunotherapeutic regimens to improve outcomes for patients with breast cancer.

摘要

乳腺癌免疫疗法是一种有效的治疗选择,像曲妥珠单抗这样的抗体疗法可使2年生存率提高50%。然而,通过疫苗接种进行的主动免疫疗法在临床上通常效果不佳。改善疫苗疗法的一种潜在方法是将乳腺癌抗原递送至树突状细胞(DC)以增强抗原呈递。为了在体内实现这一点,我们用修饰的辛德毕斯病毒糖蛋白对慢病毒载体(LV)疫苗进行假型化处理,以便它们能够将编码乳腺癌抗原α-乳白蛋白(Lalba)或erb-b2受体酪氨酸激酶2(ERBB2或HER2)的基因直接递送至驻留DC。我们假设利用这些靶向DC的慢病毒载体作为乳腺癌疫苗可增强针对乳腺癌肿瘤中自身抗原的免疫反应。实际上,与已发表的最佳疫苗方案类似,单次注射疫苗载体能够使抗原特异性CD8 T细胞比未免疫小鼠扩增4至6倍。在异种抗原环境(野生型小鼠中的LV-ERBB2)中,对这些小鼠进行免疫接种可完全抑制肿瘤生长,而在自身抗原环境(野生型小鼠中的LV-Lalba或MMTV-huHER2转基因小鼠中的LV-ERBB2)中,可降低肿瘤生长速率。这些结果表明,单次注射靶向慢病毒载体可成为一种有效的乳腺癌免疫疗法。此外,它们可与其他免疫治疗方案联合使用,以改善乳腺癌患者的治疗效果。

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