Alphavirus-Based Vaccines

Lundstrom, Kenneth

In the context of breast cancer, a DNA-based SIN vector expressing the neu gene was applied for intramuscular vaccination of mice 14 days prior to the injection of cancer cells overexpressing neu [81] . The immunization provided strong protection against tumor development. The incidence of lung metastasis from mammary fat pad tumors was reduced. Moreover, the number of lung metastases from intravenous injection of neu overexpressing cells decreased. Additionally, intradermal vaccination provided tumor protection applying 80% less plasmid than required for conventional DNA vectors. Further confirmation of successful cancer vaccination was obtained from the administration of SIN vectors expressing neu (pSINCP/neu) in a murine breast tumor model [82] . However, in this case, the prophylactic vaccine only showed efficacy when administered prior to the tumor challenge. Another approach was comprised of combining alphavirus-based delivery with the chemical anticancer agent, doxorubicin [83] . When pSINCP/neu DNA and VEE/neu particles were administered after injection of 5 mg/kg of doxorubicin, the tumor progression was significantly delayed. This phenomenon did not occur for doxorubicin alone. Similarly, a combination therapy with paclitaxel (25 mg/kg) and pSINCP/neu was ineffective. Moreover, VEE-neu particles were subcutaneously administered in a rat mammary tumor model, which resulted in the elimination of 36% of pre-existing aggressive mammary tumors [84] . The combination of dendritic cell (DC)-based cancer immunotherapy with VEE-neu particle administration induced both cellular and humoral immunity against neu in transgenic human breast tumor-bearing mice [85] . Moreover, this treatment resulted in the significant inhibition of tumor growth. Similarly, both tumor growth and pulmonary metastatic spread were significantly inhibited when mice with pre-existing tumors were subjected to five immunizations with SFV10-E VLP expressing the vascular endothelial growth factor receptor 2 (VEGFR-2) [93] . Furthermore, co-immunization with SFV particles encoding VEGFR-2 and IL-4 generated significant tumor regression in mice.