The long-term immune response after HPV16 peptide vaccination in women with low-grade pre-malignant disorders of the uterine cervix: a placebo-controlled phase II study

Abstract

The capacity of a low-dose HPV16 synthetic long-peptide vaccine (HPV16-SLP) to induce an HPV16-specific T-cell response as well as to establish long-term immunologic memory in patients with low-grade abnormalities of the cervix was determined in a placebo-controlled, double-blinded phase II study. In addition, the effect of a booster vaccination after 1 year was evaluated. Patients received either the HPV16-SLP or a placebo at the start of the study. After 1 year, the vaccinated patients were again randomized to receive the HPV16-SLP or a placebo. Patients were followed for 2 years. HPV16-specific T-cell responses were determined in pre- and post-vaccination blood samples by ELISPOT, proliferation assay and cytokine assays. We show that the HPV16-specific T-cell responses detected after vaccination are clearly due to vaccination and that reactivity was maintained for at least 2 years. Interestingly, a booster vaccination after 1 year especially augmented the HPV16-specific Th2 response. Furthermore, pre-existing immunity to HPV16 was associated with a stronger response to vaccination and with more side effects, reflected by flu-like symptoms. We conclude that two low-dose injections of HPV16-SLP can induce a strong and stable HPV16-specific T-cell response that lasts for at least 1 year. If booster vaccination is required, then polarizing adjuvant should be added to maintain the Th1 focus of the vaccine-induced T-cell response.

Vaccination against Oncoproteins of HPV16 for Noninvasive Vulvar/Vaginal Lesions: Lesion Clearance Is Related to the Strength of the T-Cell Response

“…This was also observed after peptide vaccination in renal cell cancer patients (16). In addition, some patients experienced persisting swelling and ulceration of the skin at the injection site, similar to what is found for the tetanus vaccine, hepatitis B, and BCG vaccine (17,18) and other vaccines with Montanide (19)(20)(21). Further optimization of clinical response rates and/or reduction of side effects may be achieved by using alternative adjuvants replacing Montanide, careful doseresponse studies, and by combination of vaccination with imiquimod on the lesion.…”

Nanoparticle Conjugation of Human Papillomavirus 16 E7-long Peptides Enhances Therapeutic Vaccine Efficacy against Solid Tumors in Mice

“…Cervical cancer and other HPV-induced malignancies may be attractive prototypes for immunotherapy in general and therapeutic vaccines in particular, given that the viral oncogenes encode neoantigenic oncoproteins that drive the disease. In patients with HPV + tumors, generating therapeutically efficacious CTL responses has proven difficult to achieve with classical vaccination strategies involving peptide/protein vaccines (43), including studies utilizing the HPV E7-derived SLP that produced, at best, modest CD8 + T cell responses (7)(8)(9)14). In terms of efficacy, E7 SLPs have proven to be effective in a minority of patients bearing early premalignant HPV + lesions, whereas bona fide malignancies have been largely refractory (7,10), underscoring the need for better therapeutic modalities.…”

“…Clinical responses to SLP vaccines are dependent on dendritic cells (DCs) that process SLPs into short peptides for presentation on MHC molecules (11)(12)(13) to elicit CD8 + T cell responses (7,9). Although SLPs can elicit a strong CD4 + type 1 T helper (Th1) response in patients treated with HPV vaccines, the induced CD8 + T cell counterpart is usually weaker (7)(8)(9)14). In addition to the magnitude of the CD8 + T cell response, the CD8 + T cell/regulatory T cell (Treg) ratio is a prognostic marker for HPV + cancers (15).…”

Targeted immunotherapy of high‑grade cervical intra‑epithelial neoplasia: Expectations from clinical trials (Review)

“…Inclusion rates were affected by motivational problems leading to the postponement of treatment of CIN2/3 and caused the study to be abandoned prematurely. For this reason, the same investigators conducted a randomized trial in 51 patients with low-grade premalignant disorders (LSIL or persistent HPV infection) related to at least one HR-HPV (33% HPV-16) with a two-year follow-up (23). The design was complex with a double subsequent randomization (vaccine vs. placebo) at inclusion and after one year.…”