Cipriani Barbara, Fridman Arthur, Bendtsen Claus, Dharmapuri Shridar, Mennuni Carmela, Pak Irene, Mesiti Giuseppe, Forni Guido, Monaci Paolo, Bagchi Ansu, Ciliberto Gennaro, La Monica Nicola, Scarselli Elisa
Department of Oncology, Istituto di Ricerche di Biologia Molecolare, Merck Research Laboratories, 00040 Rome, Italy.
Hum Gene Ther. 2008 Jul;19(7):670-80. doi: 10.1089/hum.2007.127.
The aim of this study was to evaluate the efficacy of genetic vaccination with rat ErbB2 antigen in a therapeutic setting for the BALB-neuT mouse model of mammary carcinoma and to establish immunological correlates with vaccine efficacy. To define an early therapeutic setting we performed imaging studies of mouse mammary glands with a high-frequency ultrasound system that allowed the diagnosis of tumor lesions before they become palpable, starting from week 13 after mouse births. An intensive immunization protocol of vaccination was implemented at this stage, consisting of four weekly DNA injections with electroporation followed by two injections of adenovirus carrying the codon usage-optimized cDNA encoding the extracellular-transmembrane domain of rat ErbB2. Immunological parameters were monitored in each individual mouse by analyzing peripheral blood leukocytes. The appearance of the first palpable tumor in vaccinated mice was delayed and there was a statistically significant time gap before additional masses developed, indicating disease stabilization. As a result of the immunization, antibodies and CD8(+) T cells to rat ErbB2 were detected and the amplitude of elicited responses correlated with the efficacy of vaccination. Moreover, the vaccination regimen specifically halted the rise in circulating myeloid suppressor cells (MSCs). All three parameters, that is, CD8(+) T cells, antibodies to rat ErbB2, and circulating MSCs, measured at the end of vaccination could be used as predictive biomarkers for future tumor development. This study emphasizes the potential of genetic vaccines for the therapeutic treatment of malignancies and suggests possible predictive biomarkers to be further validated in the clinic for the follow-up of vaccinated cancer patients.
本研究的目的是评估在BALB-neuT小鼠乳腺癌模型的治疗环境中，用大鼠ErbB2抗原进行基因疫苗接种的疗效，并建立与疫苗疗效相关的免疫指标。为了确定早期治疗环境，我们从小鼠出生后第13周开始，使用高频超声系统对小鼠乳腺进行成像研究，该系统能够在肿瘤病变可触及之前诊断出肿瘤病变。在此阶段实施了强化免疫接种方案，包括每周进行四次DNA注射并结合电穿孔，随后两次注射携带经密码子优化的cDNA的腺病毒，该cDNA编码大鼠ErbB2的细胞外跨膜结构域。通过分析外周血白细胞来监测每只小鼠的免疫参数。接种疫苗的小鼠中首次可触及肿瘤的出现被延迟，并且在出现额外肿块之前存在统计学上显著的时间间隔，表明疾病得到稳定。免疫接种的结果是检测到针对大鼠ErbB2的抗体和CD8(+) T细胞，并且引发反应的幅度与疫苗接种的疗效相关。此外，接种方案特异性地阻止了循环髓系抑制细胞(MSC)的增加。在疫苗接种结束时测量的所有三个参数，即CD8(+) T细胞、针对大鼠ErbB2的抗体和循环MSC，都可以用作未来肿瘤发展的预测生物标志物。本研究强调了基因疫苗在恶性肿瘤治疗中的潜力，并提出了可能的预测生物标志物，有待在临床上进一步验证，以用于对接种疫苗的癌症患者进行随访。
