Alphavirus-Based Vaccines

Lundstrom, Kenneth

Lung cancer has also been targeted by combined therapy with SFV-IL-12 particles and anti-CD137 monoclonal antibodies [96] . Syngeneic TC-1 lung carcinoma was inhibited after intratumoral SFV-IL-12 administration and co-stimulation with anti-CD137 mAbs. In the context of colon cancer vaccines, a SIN-based DNA vector carrying the LacZ gene was compared to conventional plasmid DNA vectors in mice with CT26.CL25 tumors [106] . Intramuscular immunization elicited immune responses at doses 100-to 1,000-fold lower for the SIN DNA replicon vector compared to the conventional CMV-promoter-based DNA-LacZ vector. Similarly, SFV particles providing VEGFR-2 expressing in vaccinated mice inhibited CT26 colon carcinoma growth [93] . Closer analysis of microvessel density demonstrated that a significant inhibition of tumor angiogenesis occurred. Additionally, when mice were co-immunized with SFV-VEGFR-2 and SFV-IL-4 particles, their survival rate was significantly enhanced. Furthermore, oncolytic SFV vectors have been used for immune stimulation in a CT26 colon tumor model [92] . Intratumoral injections led to an immediate and intense inflammatory reaction and a significant improvement in survival rates. SFV particles expressing HPV16 E6 and E7 have been subjected to prophylactic vaccine development in a murine TC-1 model for cervical cancer [107] . Pre-immunization with a low dose (10 4 particles) resulted in an HPV-specific CTL response in 50% of mice, whereas a higher dose (10 6 particles) elicited CTL responses in all animals. Furthermore, at a dose of 5 × 10 6 particles, 40% of mice were protected from tumor challenges. In another study, the SFV-enhE6,7 particle vaccine showed its potential after intravenous and intramuscular delivery, where exponentially growing tumors completely resolved [87] . Similarly, SIN virus RNA replicons expressing HPV E7 were evaluated in a TC-1 mouse model [108] . The humoral and cellular immune responses were poor, and no tumor protection was obtained; but, when the HPV E7 gene was fused to the secretory Sig protein and lysosome-associated membrane protein 1 (LAMP-1), enhanced E7-specific CD4 + helper T-cell and CD8 + cytotoxic T-cell activity was observed. Moreover, strong in vivo anti-tumor activity was induced. In another study, SIN virus particles expressing both HPV E7 and calreticulin (CRT), an endoplasmic reticulum Ca 2+ binding transporter, were tested as prophylactic vaccines [88] . Vaccinations generated antigen-specific immune responses, an anti-angiogenic effect and a strong anti-tumor activity. Furthermore, intramuscular immunization one week prior to challenge with TC-1 carcinoma cells provided protection to all treated mice. Also VEE particles expressing HPV E7 were subcutaneously injected in mice two weeks prior to cancer cell inoculation, which prevented tumor formation [89] . Furthermore, vaccination induced long-term memory, as protection was observed for challenges three months after the immunization. The therapeutic efficacy was only 67% of treated tumor-bearing mice. However, co-expression of HPV E6 and E7 from the same vector significantly enhanced the therapeutic effect [109, 110] .