Human Papillomavirus Type 16 and 18 E7-Pulsed Dendritic Cell Vaccination of Stage IB or IIA Cervical Cancer Patients: a Phase I Escalating-Dose Trial

Abstract

The safety and immunogenicity of the human papillomavirus type 16 (HPV16) or HPV18 (HPV16/18) E7 antigen-pulsed mature dendritic cell (DC) vaccination were evaluated for patients with stage IB or IIA cervical cancer. Escalating doses of autologous DC (5, 10, and 15 ؋ 10 6 cells for injection) were pulsed with recombinant HPV16/18 E7 antigens and keyhole limpet hemocyanin (KLH; an immunological tracer molecule) and delivered in five subcutaneous injections at 21-day intervals to 10 cervical cancer patients with no evidence of disease after they underwent radical surgery. Safety, toxicity, delayed-type hypersensitivity (DTH) reaction, and induction of serological and cellular immunity against HPV16/18 E7 and KLH were monitored. DC vaccination was well tolerated, and no significant toxicities were recorded. All patients developed CD4؉ T-cell and antibody responses to DC vaccination, as detected by enzyme-linked immunosorbent spot (ELISpot) and enzyme-linked immunosorbent assays (ELISA), respectively, and 8 out of 10 patients demonstrated levels of E7-specific CD8 ؉ T-cell counts, detected by ELISpot during or immediately after immunization, that were increased compared to prevaccination baseline levels. The vaccine dose did not predict the magnitude of the antibody or T-cell response or the time to detection of HPV16/18 E7-specific immunity. DTH responses to intradermal injections of HPV E7 antigen and KLH were detected for all patients after vaccination. We conclude that HPV E7-loaded DC vaccination is safe and immunogenic for stage IB or IIA cervical cancer patients. Phase II E7-pulsed DC-based vaccination trials with cervical cancer patients harboring a limited tumor burden, or who are at significant risk of tumor recurrence, are warranted.Cervical cancer is the second most common cause of cancerrelated deaths of women worldwide, with about 450,000 new cases diagnosed each year (13). In the United States and other industrialized countries, cervical cancer remains an important health problem for women, especially in underserved and minority groups (13,8). Although early-stage cervical tumors (stage IB or IIA) can be cured by radical surgery or radiotherapy with similar effectiveness, up to 20% of patients with negative lymph nodes and up to 50% of patients with positive lymph nodes may develop recurrent disease for which treatment results are poor (8). Novel therapeutic strategies that are effective in reducing the risk of recurrence in cervical cancer patients remain desperately needed.In the last few years, a multitude of epidemiological studies (29) have shown a strong and specific association, beyond reasonable doubt, between human papillomavirus (HPV) infection and cervical cancer. Accumulating evidence suggests that the majority of cervical squamous cell carcinomas and a large proportion of adenocarcinomas share a common pathogenesis involving infection with the oncogenic HPV type 16 (HPV16) and HPV18 (4, 29). The E6 and E7 transforming oncoproteins of these high-risk HPV genotypes play a crucial role in bo...

A novel CD4 T-cell epitope described from one of the cervical cancer patients vaccinated with HPV 16 or 18 E7-pulsed dendritic cells

“…Ten subjects with stage IB or IIA cervical cancer (nine HPV 16-positive, one HPV 18-positive) in this study were participants of a Phase I escalating dose trial of HPV 16/18 E7 DC vaccine described previously [26]. Five subcutaneous injections of autologous mature DC pulsed with recombinant HPV 16 or 18 E7 protein were administered 21 days apart.…”

“…Written informed consent was obtained from each participant. Seventeen T-cell lines, established by stimulating peripheral blood mononuclear cells (PBMC) with autologous mature DC pulsed with full-length HPV 16 or 18 E7 protein [26], were available from all ten subjects for this study. These PBMC were collected on day 56 after three vaccine administrations (referred to as time 1), on day 98 after five vaccine administrations (time 2), or on day 144 (without any further vaccinations; time 3).…”

HPV vaccine: Current status and future directions

“…Preliminary phase I clinical trials of HPV 16 and 18 E7 based vaccines have proven safety and immunogenicity and is awaiting phase II trials. 30 …”

Immunotherapy: An Evolving Paradigm in the Treatment of Advanced Cervical Cancer

“…63,64 In the cervical cancer arena, 2 studies have been conducted examining DC-based vaccine therapy. 65,66 In 2003, Ferrara et al 65 evaluated HPV E7 antigenloaded autologous DCs as a cellular tumor vaccine in a case series of patients with cervical cancer patients. Autologous monocyte-derived DCs were pulsed with recombinant HPV-16 E7 or HPV-18 E7 oncoprotein and administered to 15 patients with stage IV cervical cancer.…”

“…66 Escalating doses of autologous DC (5, 10, and 15 Â 10 6 cells for injection) were pulsed with recombinant HPV-16/18 E7 antigens and keyhole limpet hemocyanin (an immunologic tracer molecule) and delivered in 5 subcutaneous injections at 21-day intervals to 10 patients with cervical cancer with no evidence of disease after they underwent radical surgery. The DC Clinical Therapeutics…”