Table.

Clinical trials of human papillomavirus (HPV)-specific immunotherapy

	Delivery system	Antigen	Disease group	Immunogenicity	Clinical outcome
Double-blind placebo-controlled trial³⁴	Fusion protein (TA-CIN)	HPV-16 L2–E6–E7 fusion protein (no adjuvant)	Healthy volunteers (N=40)	Antibody, T cell, interferon γ, and ELISPOT all detected	No HPV infections
Open-label uncontrolled trial (warts not HPV-16+)³⁵	HSP fusion protein (HSP-E7)	HPV-16 E7 peptide	Genital warts (N=22)	ND	Regression of warts: 3/14 CRs and 10/14 PRs
Open-label uncontrolled trials (anal dysplasia and HPV-16+ cervical dysplasia)^36–38	Encapsulated polynucleotide (ZYC101)	HPV-16 E7	Anal and cervical dysplasia; HPV-16+; HLA-A2 (anal: N=12, cervical: N=15)	Most individuals ELISPOT positive; induction of E2-specific immunity	Regression of AIN: 3/12 PRs; regression of CIN: 5/15 CRs
Multicentre, double-blind, randomised, placebo-controlled trial (CIN2/3, any HPV type)^38,39	Encapsulated polynucleotide (ZYC101)	HPV-16 E7 peptide	CIN2/3, any HPV type (assessable N=127)	Most individuals ELISPOT positive; induction of E2-specific immunity	Lesion regression higher in patients <25 years of age; not restricted to HPV-16 or 18+ lesions
Randomised placebo-controlled trial^39,40	Protein/Iscomatrix adjuvant (E6, E7–IMX)	HPV-16 E6–E7 fusion protein	CIN (N=31)	Antibody, DTH, CTLs	HPV-type-specific reduction in HPV infection: 7/14 CRs and 7/14 PRs/no clinical regression
Open-label phase I/II uncontrolled trial⁴¹	Vaccinia virus (TA-HPV)	E6–E7 fusion protein	Late-stage cervical cancer (N=8)	CTLs (1/8), antibody (3/8)	Outcome not documented
Open-label uncontrolled trial⁴²	Vaccinia virus (TA-HPV)	E6–E7 fusion protein	Vulval HPV/VIN (N=18)	Antibody, CMI (13/18)	50% reduction in disease in 8/18; loss of viral load in 12/18
Open-label uncontrolled trial⁴³	Vaccinia virus (TA-HPV)	E6–E7 fusion protein	VIN (N=12)	T-helper cell ELISPOT increase (6/10); vaccinia response in all patients	>50% reduction in disease in 5/12
Open-label uncontrolled trial⁴⁴	Peptide/oil plus water adjuvant	E7 peptides	Refractory cervical cancer; HPV-16+; HLA-A201 (N=19)	No CTL response	2/19 stable disease
Open-label uncontrolled trial⁴⁵	Protein/algammulin adjuvant	E7–GST fusion protein	Cervical cancer (N=24)	Antibody, DTH	No alteration in natural history of disease
Open-label uncontrolled, trial HPV-16+⁴⁶	Peptide plus IFA	E7 A0201 peptide	VIN/CIN; HPV-16+; HLA-A2 (N=18)	CTLs 10/16, no DTH	3/18 CRs and 6/18 PRs
Open-label uncontrolled, trial⁴⁷	VLPs	L1	Genital warts (N=33)	Antibody, DTH	Regression of warts: 25/33 CRs
Open-label uncontrolled, trial⁴⁸	Dendritic cells	HPV-16 E7 and HPV-18 E7	Cervical cancer, stage IV (N=15)	Antibody, proliferation, ELISPOT (3/11)	No objective clinical response
Randomised placebo-controlled trial⁴⁹	Chimeric virus-like particles (CVLP)	HPV-16 1 E7 protein	CIN2/3; HPV-16 only (N=39)	Antibody, CTL	39% histological improvement in vaccinated patients vs 25% in placebo group; 59% of responders became HPV-16 DNA-negative
Open-label uncontrolled, trial⁵⁰	Peptide montanide ISA-51 adjuvant	HPV-16 E6 combined or separated from HPV-16 E7 overlapping long peptides	End-stage cervical cancer (N=35)	ELISPOT	Immunity against E6 in patients vaccinated with E6 and E7 at the same site; greater response to E7 in patients vaccinated with E6 in one limb and with E7 in a different limb
Open-label uncontrolled, trial⁵¹	DNA vaccine	Sig-E7(detox)-heat-shock protein-70 fusion protein	CIN2/3; HPV-16+; (N=15)	ELISPOT	Complete histological regression in 33% (3/9) in the highest dose cohort; new responses to E7 at 6 months

IFN=interferon. ELISPOT=enzyme-linked immunosorbent spot. ND=not done. CR=complete response. PR=partial response. HSP=heat shock protein. HLA-A2=human leucocyte antigen serotype A2. AIN=anal intraepithelial neoplasia. CIN=cervical intraepithelial neoplasia. DTH=delayed hypersensitivity reaction. CTL=cytotoxic T lymphocyte. VIN=vulvar intraepithelial neoplasia. CMI=cell-mediated immunity. GST=glutathione-S-transferase. IFA=incomplete Freund’s adjuvant. VLP=virus-like particle.