Dendritic cell-based

Wide variety of modes of administration (i.e., direct injection, gene gun, intranasal, and biojector) Sustained expression of antigen on MHC-peptide complexes (vs peptide/ protein vaccines) Noninfectious and transient (no risks of chromosomal integration or cellular transformation) Multiple immunizations possible RNA replicons replicate within the cell to enhance antigen expression Multiple vectors available Highly immunogenic (uses the most potent Antigen-presenting cell [APC])

Generation of large quantities of DCs possible Multiple methods of antigen loading available

Table 5 (Continued)

Disadvantages Clinical trials

Study to assess the safety and efficacy of ZYClOla, an encapsulated plasmid DNA vaccine encoding fragments derived from the E6 and E7 proteins of HPV-16 and -18, in women with high-grade CIN (Grade II or III) (99)

Unstable to store and handle Cumbersome to prepare Difficult to produce in large quantities

Labor-intensive, costly, ex vivo, individualized cell processing Variable quality control and lack of standard criteria for quality of vaccines Do not necessarily home to draining lymph nodes

Study of HPV-16 and -18 E7 antigen-loaded autologous dendritic cell vaccination in a small series of cervical cancer patients with recurrent disease refractory to standard treatment modalities (129,130)

Tumor cell-based

Potency can be enhanced by gene transduction or cytokine treatment Useful if tumor antigen is unknown Potency can be enhanced by gene transduction or cytokine treatment Likely to express relevant tumor antigens

Tolerization by immature DCs possible

Safety concerns regarding injection of tumor cells into patients Labor intensive production Weak antigen presentation by tumor cells Requires availability of tumor cell lines or autologous tumor cells of the other therapeutic vaccines under clinical evaluation, the immune and clinical responses to vaccination have not been consistent. The immune response to the pep-tide epitopes encoded within the DNA vaccine was increased in 10 of the 12 individuals with anal dysplasia (97). Five out of 15 women with CIN-2/3 had complete histological responses and 11 out of 15 women with CIN-2/3 had human papillo-mavirus-specific T-cell responses (98). The next generation ZYC-101 vaccine, ZYC-101a (ZYCOS Inc), contains a plasmid DNA encoding both HPV-16 and HPV-18 E6 and E7 epitopes. A recent phase II trial demonstrates that a prospectively defined subgroup of younger women have a significantly higher rate of disease resolution when treated with ZYC-101a than when administered placebo (99). However, when comparing the effect of placebo and ZYC-101a in the whole population studied, no significant difference was observed.

The limited immunogenicity of DNA vaccines may potentially be enhanced by fusion of the antigen with molecules that improve antigen processing and promote immune recognition. For example, clinical trials of HPV16 E7 expressed with a signal sequence and fused to a heat shock protein are ongoing at Johns Hopkins University. In preclinical studies the signal sequence enhances antigen processing of the E7 and its release from the cell whereas heat shock protein binds with and activates dendritic cells. Fusion of E7 to calreticulin also produces similar phenomena and may provide antiangiogenic activities.

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