ABSTRACT
Cervical cancer is one of the most common causes of cancer-related death in women. As a result of several recent advances in molecular biology, the association between human papillomavirus (HPV) infection and cervical cancer has been firmly established, and the oncogenic potential of certain HPV types has been clearly demonstrated. Several lines of evidence suggest the importance of the host's immune response, especially cellular immune response, in the pathogenesis of HPV-associated cervical lesions. These observations form a compelling rationale for the development of vaccine therapy to combat HPV infection. Both prophylactic and therapeutic HPV vaccine strategies are being developed. Prophylactic strategies currently under investigation focus on the induction of effective humoral immune responses against subsequent HPV infection. In this respect, impressive immunoprophylactic effects have been demonstrated in animals using papillomavirus-like particles (VLPs). VLPs are antigenic and protective, but are devoid of any viral DNA that may be carcinogenic to the host. For treatment of existing HPV infection, techniques to improve cellular immunity by enhancing viral antigen recognition are being studied. For this purpose, the oncogenic proteins E6 and E7 of HPV-16 and -18 are the focus of current clinical trials for cervical cancer patients. The development of successful HPV-specific vaccines may offer an attractive alternative to existing screening and treatment programs for cervical cancer.
Subject(s)
Papillomaviridae/immunology , Papillomavirus Infections/therapy , Papillomavirus Vaccines , Uterine Cervical Neoplasms/prevention & control , Uterine Cervical Neoplasms/therapy , Viral Vaccines , Animals , Female , Humans , Immunity, Cellular , Immunotherapy, Active , Papillomavirus Infections/prevention & control , Tumor Virus Infections/prevention & control , Tumor Virus Infections/therapy , Uterine Cervical Neoplasms/virology , Viral Vaccines/therapeutic useABSTRACT
When intracellular viral proteins are degraded, only a limited number of peptide epitopes are capable of eliciting specific CD8+ cellular immune responses for a given human leukocyte antigen (HLA) haplotype. We sought to induce CD8+ T-lymphocyte (CTL) responses to human papillomavirus-16 (HPV-16) E6 and E7 proteins using a recombinant E6/E7 fusion protein and autologous human dendritic cells (DCs). CTLs were generated by in vitro stimulation using a recombinant HPV-16 E6/E7 fusion protein and autologous DCs from a healthy HLA-A*0201 donor. CTL specificity was assessed by cytokine release assays when the cells were reacted with autologous DC targets coincubated with the E6/E7 fusion protein. These CTLs were also reacted with the immunodominant E7 peptides (E711-20 and E7(86-93)) and DCs as a target. As a negative control, DCs were incubated with or without an irrelevant control protein (Helicobacter pylori) as target for the E6/E7-induced CTLs. The E6/E7-induced CTLs were capable of specific recognition of target DCs coincubated with E6/E7 but not the control protein. When E6/E7-specific CTLs were reacted with DCs and either E7(11-20) or E7(86-93), specific peptide recognition was also detected. These data demonstrate that specific CTLs can be elicited using autologous human DCs and a HPV-16 E6/E7 fusion protein. Therefore, extracellular viral proteins seem to be engulfed and processed by DCs; then the immunodominant HLA-A2-restricted peptides become available for CD8+ T-lymphocyte recognition. These data suggest that vaccine strategies using recombinant viral proteins may overcome the limitation of peptide epitopes for specific HLA haplotypes and may, therefore, permit more generalized clinical application.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Oncogene Proteins, Viral/immunology , Repressor Proteins , Antigen Presentation , Cells, Cultured , Histocompatibility Antigens Class I/biosynthesis , Histocompatibility Antigens Class I/immunology , Humans , Leukocytes, Mononuclear/immunology , Lymphocyte Subsets/immunology , Papillomavirus E7 Proteins , Recombinant Fusion Proteins/immunologyABSTRACT
Human papillomavirus (HPV) infection has been causally associated with cervical cancer. We tested the effectiveness of an HLA-A*0201-restricted, HPV-16 E7 lipopeptide vaccine in eliciting cellular immune responses in vivo in women with refractory cervical cancer. In a nonrandomized Phase I clinical trial, 12 women expressing the HLA-A2 allele with refractory cervical or vaginal cancer were vaccinated with four E786-93 lipopeptide inoculations at 3-week intervals. HLA-A2 subtyping was also performed, and HPV typing was assessed on tumor specimens. Induction of epitope-specific CD8+ T-lymphocyte (CTL) responses was analyzed using peripheral blood leukapheresis specimens obtained before and after vaccination. CTL specificity was measured by IFN-gamma release assay using HLA-A*0201 matched target cells. Clinical responses were assessed by physical examination and radiographic images. All HLA-A*0201 patients were able to mount a cellular immune response to a control peptide. E786-93-specific CTLs were elicited in 4 of 10 evaluable HLA-A*0201 subjects before vaccination, 5 of 7 evaluable HLA-A*0201 patients after two vaccinations, and 2 of 3 evaluable HLA-A*0201 cultures after all four inoculations. Two of three evaluable patients' CTLs converted from unreactive to reactive after administration of all four inoculations. There were no clinical responses or treatment toxicities. The ability to generate specific cellular immune responses is retained in patients with advanced cervical cancer. Vaccination with a lipidated HPV peptide epitope appears capable of safely augmenting CTL reactivity. Although enhancements of cellular immune responses are needed to achieve therapeutic utility in advanced cervical cancer, this approach might prove useful in treating preinvasive disease.
Subject(s)
Cancer Vaccines/therapeutic use , Carcinoma, Squamous Cell/immunology , Carcinoma, Squamous Cell/therapy , Epitopes/immunology , Epitopes/therapeutic use , Oncogene Proteins, Viral/immunology , Uterine Cervical Neoplasms/immunology , Uterine Cervical Neoplasms/therapy , Vaginal Neoplasms/immunology , Vaginal Neoplasms/therapy , Adult , Cancer Vaccines/immunology , Epitopes/administration & dosage , Epitopes, T-Lymphocyte/biosynthesis , Epitopes, T-Lymphocyte/immunology , Female , Humans , Immunity, Cellular/immunology , Immunotherapy, Active , Lipids/administration & dosage , Middle Aged , Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/therapy , Papillomavirus E7 Proteins , Peptides/administration & dosage , Peptides/immunology , T-Lymphocytes, Cytotoxic/immunologyABSTRACT
Therapeutic and prophylactic vaccines that harness the potential of the immune system against a number of gynecologic cancers are now being developed. The therapeutic vaccines coerce the cellular components of the immune system to attack malignant tissue. The prophylactic vaccines induce the production of antibodies capable of neutralizing viral antigens before they infect host cells. However, malignant tumors are usually a heterogeneous mixture of different malignant cells, and it is likely that variant tumor clones within a tumor may not express the target antigen or may possess defects in their antigen-presenting mechanism. Ultimately, therapeutic vaccines may be better suited for the treatment of preinvasive disease or for use as an adjuvant following primary therapy. The prospects for developing efficacious vaccines to treat or prevent cervical, ovarian, uterine, and other gynecologic cancers are promising, however. This article describes the methodology of and rationale for these vaccines.
Subject(s)
Cancer Vaccines/therapeutic use , Genital Neoplasms, Female/therapy , Immunotherapy, Active/methods , Antibodies, Neoplasm/immunology , Antigens, Neoplasm/immunology , Clinical Trials as Topic , Combined Modality Therapy , Disease Progression , Female , Genetic Therapy/methods , Genital Neoplasms, Female/immunology , Genital Neoplasms, Female/pathology , Humans , T-Lymphocytes/immunology , Treatment OutcomeABSTRACT
PURPOSE: Steroid doses similar to those used to prevent paclitaxel-associated hypersensitivity reactions and cisplatin-induced nausea have been associated with hypothalamic-pituitary-adrenal (HPA) axis suppression. We assessed HPA function in patients receiving high-dose steroids as part of their chemotherapy regimen for epithelial ovarian cancer. PATIENTS AND METHODS: From January to July 1994, a cross-sectional study of HPA function was performed on patients receiving dexamethasone (DEX) as part of their paclitaxel and cisplatin chemotherapy regimen (n = 9). Patients received 20 mg of DEX orally, 6 and 12 hr prior to paclitaxel (135 mg/m2) and 10-20 mg intravenously before cisplatin (50-100 mg/m2). In addition, patients received approximately 12 mg/day of DEX orally for 4 days after their chemotherapy as an antiemetic. HPA integrity was evaluated by the administration of synthetic adrenocorticotropic hormone (ACTH). The ACTH stimulation test was performed 11-19 days after the completion of the course of DEX. Patients had fasting baseline cortisol levels drawn at approximately 0800 followed by a 25-unit intravenous injection of ACTH. Post-ACTH cortisol levels were repeated at 30 and 60 min. RESULTS: The mean (+/- SEM) fasting baseline level of cortisol was 12.4 +/- 2.3 micrograms/dl (normal, 7-23 micrograms/dl). At 30 min following ACTH administration, the mean cortisol level rose 17.1 micrograms to 29.5 +/- 1.8 micrograms/dl; at 60 min it rose 21.4 micrograms to 33.8 +/- 2.5 micrograms/dl [P < 0.001] (normal increase 9-39 micrograms). All patients demonstrated a sufficient increase in their plasma cortisol after ACTH stimulation, indicating normal HPA function on the days tested. However, there was a significant trend toward lower increases in plasma cortisol at 30 and 60 min as the interval from ACTH stimulation testing to the DEX regimen decreased (r = 0.986; P < 0.0001). The chemotherapy cycle number had no impact on cortisol response in the multivariate analysis. Based on multiple linear regression, HPA function may be suppressed for approximately 8 days, but up to 14 days from the start of this DEX regimen. CONCLUSION: Current steroid regimens prescribed with chemotherapy transiently decrease HPA function, but do not appear to inhibit the HPA axis long term. HPA function may be suppressed for approximately 8 days from the commencement of chemotherapy cycles involving DEX. Patients presenting within the first 8 days of a chemotherapy cycle using steroids with symptoms attributable to HPA suppression may benefit from HPA axis testing.