Biomedical Engineering Reference
In-Depth Information
development.of.cervical.cancer.is.closely.associated.with.infection.by.high-risk.types.of.
human. papillomaviruses. (HPVs). 37 . Studies. have. shown. that. HPV16. is. the. predominant.
subtype.of.both.cancers,.accounting.for.46%-63%.of.cervical.cancer.cases.and.90%.of.head.
and. neck. cancer. cases. 38,39 . In. addition,. HPV-associated. head. and. neck. cancer. affects. as.
many.as.115,000.people.each.year.globally. 38,40 .The.rationale.for.this.vaccine.is.to.prevent.
the.progression.of.HPV-infected.cells.to.malignant.cancer..Although.preventative.vaccines.
(Gardasil. and. Cervarix). are. suficient. to. prevent. about. 70%-80%. of. all. cervical. cancers,.
they.are.not.effective.in.controlling.existing.HPV.infections.or.HPV-associated.lesions. 41
Inovio.constructed.DNA.vaccine.plasmids.that.express.either.the.HPV16.E6.and.E7.pro-
teins. or. the. HPV18. E6. and. E7. proteins,. which. are. responsible. for. the. transformation. of.
cells.and.are.required.for.the.maintenance.of.HPV-associated.malignancies,.making.them.
ideal.immunotherapeutic.targets. 42,43 .To.target.both.HPV16.and.18,.this.group.formulated.
VGX™-3100,.which.is.a.combination.of.the.two.aforementioned.plasmids.and.targets.both.
the.E6.and.E7.proteins..As.part.of.an.ongoing.phase.I.clinical.trial.in.the.United.States,.
Inovio.immunized.adult.females.with.postsurgical.or.ablative.treatment.of.grade.2.or.3.
cervical.intraepithelial.neoplasia.(CIN).with.varying.concentrations.of.VGX-3100.via.intra-
muscular.injection.followed.by.electroporation..Although.the.study.is.currently.ongoing,.
Inovio.has.thus.far.observed.no.adverse.effects.with.the.vaccine.and.is.currently.complet-
ing.the.analysis.of.the.immune.responses.from.VGX-3100.immunization;.the.initial.analy-
ses. show. that. the. vaccination. scheme. can. generate. signiicant. antigen-speciic. immune.
responses.in.these.patients.
There.have.several.other.studies.that.also.delivered.DNA.vaccines.with.electroporation..
ChronVac-C,.a.HCV.NS3/4A.DNA.vaccine,.has.been.evaluated.in.humans;.this.study.was.
conducted.by.Tripep.AB.and.was.the.world's.irst.clinical.trial.of.an.HCV.DNA.vaccine.
delivered.by.in.vivo electroporation. 44 .Although.no.direct.comparisons.between.DNA.and.
DNA.+.electroporation.were.conducted,.two.of.three.patients.in.the.0.5.mg.and.1.5.mg.vac-
cine.groups.responded.to.the.vaccine.as.measured.by.an.increase.in.HCV-speciic.cellular.
immune.responses.and.a.reduction.in.viral.load.
Two. other. studies,. however,. directly. compared. the. delivery. of. DNA. alone. and. DNA.
plus.electroporation..Low.et.al..immunized.HLA-A2 +. patients.with.known.prostate.cancer.
with.the.p.DOM-PSMA 27 .vaccine,.which.encodes.a.domain.(DOM).of.fragment.C.of.teta-
nus.toxin.fused.to.the.prostate-speciic.membrane.antigen.(PSMA). 45 .This.study.delivered.
the. p.DOM-PSMA 27 . vaccine. intramuscularly. with. or. without. electroporation,. and. mea-
sured. anti-DOM. antibody. responses.. Importantly,. while. DNA. alone. increased. the. anti-
DOM. antibody. response. by. 1.7-fold,. DNA. plus. electroporation. increased. the. response.
by. 24.5-fold,. and. the. response. with. electroporation. persisted. to. 18. months. of. follow-up,.
suggesting. a. dramatic. increase. in. antibody. responses. in. humans. with. electroporation..
The.second.study.was.from.the.Aaron.Diamond.AIDS.Research.Center.(ADARC).and.the.
International.AIDS.Vaccine.Initiative.(IAVI),.and.evaluated.the.cellular.immune.response.
induced.from.immunization.with.ADVAX,.an.HIV.DNA.vaccine. 46 .This.study.also.com-
pared. the. responses. from. patients. immunized. with. ADVAX. alone. or. with. a. combina-
tion.of.ADVAX.and.electroporation..Importantly,.the.authors.reported.that.while.none.of.
the.subjects.who.received.ADVAX.alone.generated.detectable.cellular.immune.responses.
after.three.injections,.all.of.the.subjects.who.received.ADVAX.with.electroporation.gener-
ated.a.modest.level.of.antigen-speciic.immune.responses..Therefore,.both.of.these.studies.
strongly. suggest. the. importance. of. delivering. DNA. vaccines. with. electroporation,. and.
increase. the. anticipation. of. the. results. of. other. studies. involving. DNA. vaccines. deliv-
ered.via.electroporation..A.list.of.such.studies.that.are.in.clinical.evaluation.is.shown.in.
Table 14.3.
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