DNA vaccines to attack cancer

Abstract

Delivery of antigens by injection of the encoding DNA allows access to multiple antigen-presenting pathways. Knowledge of immunological processes can therefore be used to modify construct design to induce selected effector functions. Expression can be directed to specific intracellular sites, and additional genes can be fused or codelivered to amplify responses. Therapeutic vaccination against cancer adds a requirement to overcome tolerance and to activate a weakened immune repertoire. Induction of CD4 ؉ T helper cells is critical for both antibody and T cell effector responses. To activate immunity against tumor antigens, we fused the tumor-derived sequences to genes encoding microbial proteins. This strategy engages T helper cells from the large antimicrobial repertoire for linked help for inducing antibody against cell-surface tumor antigens. The principle of linked T cell help also holds for induction of epitope-specific antitumor CD8 ؉ T cells, but the microbial sequence has to be minimized to avoid competition with tumor antigens. Epitope-specific DNA vaccination leads to powerful antitumor attack and can activate immunity from a profoundly tolerized repertoire. Vaccine designs validated in preclinical models are now in clinical trial with immune responses detected against both tumor antigens and fused microbial antigens. DNA priming is highly efficient, but boosting may benefit from increased antigen expression. Physical methods including electroporation provide increased expression without introducing additional competing antigens. A wide range of cancers can be targeted, and objective assays of response will determine efficacy.

DNA Vaccines: Progress and Challenges

“…Patient-specific DNA vaccines for therapy of B cell lymphomas and multiple myelomas based on single-chain Fv's derived from individual patients' cancers were shown to be effective in animal models and are being studied in clinical trials (reviewed in Ref. 76).…”

Human Major Histocompatibility Complex (MHC) Class I Molecules with Disulfide Traps Secure Disease-related Antigenic Peptides and Exclude Competitor Peptides

“…Thus these HLA-I SCTs clearly passed ER quality control, and linkers were accommodated such that the proper folding was detected by mAbs specific for the native, fully assembled HLA-I molecules. It is noteworthy that a construct similar to our G280-9V.␤ 2 m.A2 SCT was expressed as a recombinant protein (19); however, for certain applications such as DNA vaccination (46,47), it was critical to verify cell surface expression in mammalian cells where the SCT faces competition with endogenous ␤ 2 m, peptides, and molecular chaperones.…”

Plasmid-based gene therapy of diabetes mellitus

“…DNA vaccination has been studied as a means of generating immunity against the antigens of infectious agents or tumors [39][40][41][42][43] owing to the simplicity, versatility and safety of the method. In the vast majority of cases, DNA has been delivered in the form of an expression plasmid, either naked or complexed to other molecules, although other types of vectors can be used.…”