通过使用两种不同载体的初免/加强免疫方案提高重组抗癌疫苗的疗效。

Enhancing efficacy of recombinant anticancer vaccines with prime/boost regimens that use two different vectors.

作者信息

Irvine K R, Chamberlain R S, Shulman E P, Surman D R, Rosenberg S A, Restifo N P

机构信息

Surgery Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20892-1502, USA.

出版信息

J Natl Cancer Inst. 1997 Nov 5;89(21):1595-601. doi: 10.1093/jnci/89.21.1595.

DOI:10.1093/jnci/89.21.1595

PMID:9362157

Abstract

BACKGROUND

The identification of tumor-associated antigens and the cloning of DNA sequences encoding them have enabled the development of anticancer vaccines. Such vaccines target tumors by stimulating an immune response against the antigens. One method of vaccination involves the delivery of antigen-encoding DNA sequences, and a number of recombinant vectors have been used for this purpose. To optimize the efficacy of recombinant vaccines, we compared primary and booster treatment regimens that used a single vector (i.e., homologous boosting) with regimens that used two different vectors (i.e., heterologous boosting).

METHODS

Pulmonary tumors (experimental metastases) were induced in BALB/c mice inoculated with CT26.CL25 murine colon carcinoma cells, which express recombinant bacterial beta-galactosidase (the model antigen). Protocols for subsequent vaccination used three vectors that encoded beta-galactosidase--vaccinia (cowpox) virus, fowlpox virus, naked bacterial plasmid DNA. Mouse survival was evaluated in conjunction with antibody and cytotoxic T-lymphocyte responses to beta-galactosidase.

RESULTS

Heterologous boosting resulted in significantly longer mouse survival than homologous boosting (all P<.0001, two-sided). Potent antigen-specific cytotoxic T lymphocytes were generated following heterologous boosting with poxvirus vectors. This response was not observed with any of the homologous boosting regimens. Mice primed with recombinant poxvirus vectors generated highly specific antibodies against viral proteins.

CONCLUSIONS

The poor efficacy of homologous boosting regimens with viral vectors was probably a consequence of the induction of a strong antiviral antibody response. Heterologous boosting augmented antitumor immunity by generating a strong antigen-specific cytotoxic T-lymphocyte response. These data suggest that heterologous boosting strategies may be useful in increasing the efficacy of recombinant DNA anticancer vaccines that have now entered clinical trials.

摘要

背景

肿瘤相关抗原的鉴定以及编码这些抗原的DNA序列的克隆推动了抗癌疫苗的发展。此类疫苗通过刺激针对抗原的免疫反应来靶向肿瘤。一种疫苗接种方法涉及递送编码抗原的DNA序列，并且已经使用了多种重组载体来实现这一目的。为了优化重组疫苗的疗效，我们比较了使用单一载体的初次和加强治疗方案（即同源加强）与使用两种不同载体的方案（即异源加强）。

方法

将表达重组细菌β-半乳糖苷酶（模型抗原）的CT26.CL25小鼠结肠癌细胞接种到BALB/c小鼠中，诱导产生肺部肿瘤（实验性转移瘤）。后续疫苗接种方案使用三种编码β-半乳糖苷酶的载体——痘苗（牛痘）病毒、禽痘病毒、裸露的细菌质粒DNA。结合对β-半乳糖苷酶的抗体和细胞毒性T淋巴细胞反应评估小鼠存活率。