Table 3.
Different strategies to enhance the potency of therapeutic HPV DNA vaccines
| Strategy | Approach | References | Relevant clinical trials (NCT numbers) |
|---|---|---|---|
| [1] Increasing DC uptake of HPV antigens | |||
| [I] Routes of administration | [a] ID and subdermal administration via gene gun [b] Electroporation-mediated IM or mucosal administration [c] ID administration followed by laser treatment [d] Microspheres and nanoparticle-based delivery systems [e] Other novel delivery systems |
60–66 65, 67–70, 72–74 75, 76 77–81 82–84 |
02139267; 02411019; 03185013; 02241369 |
| [II] Intercellular spreading of HPV antigens to DCs | Fuse HPV antigens with [a] VP22 [b] MVP22 |
85–91, 93, 144 94 |
|
| [III] Targeting antigens directly to DCs | Fuse HPV antigens with [a] HSP70 [b] CTLA4 |
95–98 100–105 |
00788164 |
| [IV] Enhancing the release of HPV antigens into DC Surroundings | [a] Chemotherapy using • DMXAA • EGCG • Apigenin • Cisplatin • Bortezomib [b] Radiation |
106, 111 107 108 109 109, 110 112 |
|
| [2] Improving HPV antigen expression, processing, and presentation in DCs | |||
| [I] Enhancing antigen expression in transfected DCs | [a] Enhancing transcription of HPV DNA by co-administering demethylating agents [b] Enhancing translation of HPV mRNA: • Codon optimization • Kozak sequence addition |
113–117 73, 115, 119, 120 121, 122 |
03185013; 03180684 |
| [II] Enhancing MHC I and MHC II expression in DCs | Co-administer: [a] CIITA [b] HDACi |
123–125 126–130 |
|
| [III] Enhancing antigen processing through the MHC I pathway cross-presentation | [a] Targeting antigens for proteosomal degradation by way of fusion with • PVX-CP • γ-tubulin or ubiquitin • Destabilizing mutations [b] Targeting antigens to the ER by way of fusion with • Signal peptides • ER chaperone proteins (CRT) [c] Targeting antigens to the cytoplasm by way of fusion with • ETA • Flt3L |
132, 133 132–136 137 138–141 66, 142–149 150, 151 72, 152–155 |
02411019; 02139267; 02596243 |
| [IV] Enhancing antigen processing through the MHC II pathway | Fuse HPV antigens with LAMP-1 | 156–160 | |
| [V] Bypassing antigen processing by the MHC I pathway | Fuse HPV antigens with SCT | 161–163 | |
| [3] Enhancing DC function and survival, DC and T-cell interactions, and T-cell function survival | |||
| [I] Enhancing DC function and survival | [a] Enhance DC cross-priming abilities by: • Co-administering TLR agonists and DC-activating cytokines (GM-CSF) • Fusing HPV antigens with HSV-1 gD [b] Prolonging the survival of antigen-expressing DCs by way of co-administering • BCL-xL • CTGF • Bax and Bak RNAi |
167–177 172, 178 180 181 182 |
03206138; 03180684 |
| [II] Boosting DC and T-cell interactions | Generate CD4+ T-cell help by way of co-administering • Ii-PADRE • CD4+ T-cell epitopes (TTFC and BPV-1 L1 or L2) • Xenogeneic MHC I |
184–187 171, 188 190 |
|
| [III] Promoting T-cell function and survival | [a] Enhance T-cell development and maintenance by way of co-administering • IL-2 • Anti-4-1BB • IL-7 • IL-12 [b] Target effector T-cells to tumor sites by co-administering IP-10 [c] Reducing apoptosis of T-cells • Anti-PD-L1 blockage • FasL blockage |
191, 192 193, 194 195, 196 197 203–205 208 209–212 |
02860715; 0320613 02172911; 03162224; 02241369 03162224 |
| [IV] Enhancing immune responses through elimination of Tregs | [a] CTX [b] Monoclonal anti-CD25 |
216, 217 216, 217 |
|
BCL-xL, B-cell lymphoma-extra large; BPV-1, bovine papillomavirus type 1; CIITA, major histocompatibility complex (MHC) class II transactivator; CRT, calreticulin; CTGF, connective tissue growth factor; CTLA4, cytotoxic T-lymphocyte antigen 4; CTX, cyclophosphamide; DMXAA, 5,6-dimethylxanthenon-4-acetic acid; EGCG, epigallocathechin-3-gallate; ER, endoplasmic reticulum; ETA, exotoxin A; HDACi, histone deacetylase inhibitor; HSP70, heat shock protein 70; HSV-1, herpes simplex virus type 1; ID, intradermal; Ii-PADRE, invariant Pan HLA-DR reactive epitope; IM, intramuscular; LAMP-1, lysosomal-associated membrane protein type 1; MHC, major histocompatibility complex; NCT, National Clinical Trial; PD-L1, programmed death-ligand 1; PVX-CP, potato virus X coat protein; SCT, single-chain trimers; TLR, toll-like receptor; Tregs, regulatory T-cells; TTFC, tetanus toxin fragment C.