DNA vaccination against tumors

Abstract

DNA vaccines have been used to generate protective immunity against tumors in a variety of experimental models. The favorite target antigens have been those that are frequently expressed by human tumors, such as carcinoembryonic antigen (CEA), ErbB2/neu, and melanoma-associated antigens. DNA vaccines have the advantage of being simple to construct, produce and deliver. They can activate all arms of the immune system, and allow substantial flexibility in modifying the type of immune response generated through codelivery of cytokine genes. DNA vaccines can be applied by intramuscular, dermal/epidermal, oral, respiratory and other routes, and pose relatively few safety concerns. Compared to other nucleic acid vectors, they are usually devoid of viral or bacterial antigens and can be designed to deliver only the target tumor antigen(s). This is likely to be important when priming a response against weak tumor antigens. DNA vaccines have been more effective in rodents than in larger mammals or humans. However, a large number of methods that might be applied clinically have been shown to ameliorate these vaccines. This includes in vivo electroporation, and/or inclusion of various immunostimulatory molecules, xenoantigens (or their epitopes), antigen-cytokine fusion genes, agents that improve antigen uptake or presentation, and molecules that activate innate immunity mechanisms. In addition, CpG motifs carried by plasmids can overcome the negative effects of regulatory T cells. There have been few studies in humans, but recent clinical trials suggest that plasmid/virus, or plasmid/antigen-adjuvant, prime-boost strategies generate strong immune responses, and confirm the usefulness of plasmid-based vaccination.

‘Survival gene’ Bcl-xl potentiates DNA-raised antitumor immunity

“…33,34 Targeting of DCs with GM-CSF and Flt3L DNA increased DC numbers in vivo and enhanced Ag-specific CD4+ T-cell responses. 35 The DNA vaccine was also designed to encode DC maturation signals.…”

CCL19 as an adjuvant for intradermal gene gun immunization in a Her2/neu mouse tumor model: improved vaccine efficacy and a role for B cells as APC

“…[4][5][6][7] Although DNA vaccines have been very successful in inducing antigen-specific immune responses in mice, [8][9][10] immunogenicity in humans and large animals has so far been largely disappointing. 3,9,11 The reasons are diverse, but are mostly related to topics such as dosing, application route, tissue distribution and differences in toll-like receptor (TLR) expression patterns between mice and humans. 12 New experimental approaches aimed at amplifying the immune responses induced by DNA vaccines are therefore warranted.…”

Vaccination with liposome–DNA complexes elicits enhanced antitumor immunity

“…[1][2][3][4][5] Impressive clinical responses to cancer vaccines have been observed in a few recent human clinical trials, although the overall track record for cancer vaccines is less impressive. [6][7][8] It is apparent therefore that a number of hurdles remain and there is still a strong need for improvements in tumor vaccine design before they realize their full potential.…”

“…Previous tumor vaccine strategies have included immunization with whole tumor cell or tumor lysate vaccines, peptide vaccines, dendritic cell (DC) vaccines, viralvectored vaccines and plasmid DNA vaccines. 5,[10][11][12][13][14][15][16][17][18][19][20] Plasmid DNA vaccines are attractive because they are relatively easy to engineer and produce and are safe to administer to humans. 1,5,[21][22][23][24] A number of studies have reported the use of plasmid DNA-based vaccines for eliciting antitumor immunity in mice.…”

“…5,[10][11][12][13][14][15][16][17][18][19][20] Plasmid DNA vaccines are attractive because they are relatively easy to engineer and produce and are safe to administer to humans. 1,5,[21][22][23][24] A number of studies have reported the use of plasmid DNA-based vaccines for eliciting antitumor immunity in mice. [25][26][27][28][29][30] However, induction of therapeutic antitumor activity, especially against tumor metastases to the lungs, has been more difficult to achieve using DNA vaccines.…”