Trial Title:
The Development of Human Papillomavirus Type 16 E7-Specific Human Immunologic Assays in Non-HLA2 Type Human Being
NCT ID:
NCT00155792
Condition:
Cervical Cancer
Conditions: Official terms:
Uterine Cervical Neoplasms
Conditions: Keywords:
ervical cancer, human papillomavirus, immunotherapy
Study type:
Observational
Overall status:
Unknown status
Study design:
Time perspective:
Other
Summary:
Cervical cancer the most frequent neoplasm and the third mortality rate of malignancies
of the women in the world. It results in about 200,000 women dying of cervical cancer
each year worldwide. The available forms of treatment-surgery, radiation therapy, and
chemotherapy are all cytoreductive treatment modalities, so in addition to killing
cancerous cells, healthy cells are also destroyed in the process. Indeed, there is a need
to decrease the incidence of cervical cancer and develop better forms of its treatment.
Human papilloma viruses (HPV) have been consistently implicated in causing cervical
cancer especially those high-risk types (HPV 16,18,31,45) have been strongly associated
with cervical cancer. HPV 16 was found in more than 50% of cervical cancer tissues. So
the host immune response plays an important role in determining the regression of
cervical abnormality or persistence and progression to malignancy via targeting HPV.
The ideal cancer treatment should be able to eradicate systemic tumors at multiple sites
in the body while having the specificity to discriminate between neoplastic and
nonneoplastic cells. In this regard, antigen-specific cancer immunotherapy represent an
attractive approach for cancer treatment. It is now clear that major histocompatibility
complex (MHC) class I restricted CD8+ T cytotoxic cells are critical to the generation of
antitumor immunity. Cell-mediated responses are critical in anti-tumor immunity.
By cooperating with Dr. TC Wu in Johns Hopkins Medical Institutes, we have recently
developed some E7-specific cancer vaccines of different strategies such as DNA, or
replication-defective SINrep5 virus. We found that these E7-chimeric DNA vaccines are
capable of preventing and treating the growth of murine model tumors expressing E7. These
positive results from the preclinical murine models have encouraged us to focus on the
development of cancer vaccine and immunotherapy and apply these vaccines to human
subjects. However, it is very important to set up various E7-specific immunologic assays
of human being to evaluate the effect of cancer vaccine or immunotherapy in the future
clinical trials. So we would like to provide this proposal to address on the development
of HPV 16 E7-specific immunologic assays in human being.
Detailed description:
HPV and Cervical Cancers Human papillomaviruses (HPV) are small, nonenveloped DNA viruses
which induce epithelial tumors of skin or mucosa. The majority of tumors are benign, show
limited growth and usually regress spontaneously. However, a number of human
papillomaviruses induce tumors that may eventually progress to carcinomas. The genital
HPV types 16 and 18, and less frequently, types 31, 33, 35, 45, 51 and 56, have been
implicated in the etiology of cervical and other anogenital cancers. Approximately
500,000 women worldwide develop cervical cancer yearly and it is the second leading cause
of death from cancer in women [1]. In developed countries, cancer of the cervix ranks
behind cancers of the breast, lung, uterus, and ovaries and accounts for 7% of all female
cancers. In the United States, there are about 4,800 deaths annually from cervical cancer
[2]. The evidence linking HPVs to anogenital cancer comes from epidemiologic and
laboratory studies. More than 90% of cervical cancers and their precursors, so-called
cervical intraepithelial neoplasia (CIN), contain human papillomavirus (HPV) DNA
sequences [3]. The HPV types found in cancer cells have transforming activity in in vitro
studies [4] and the viral transforming proteins, E6 and E7, are consistently expressed in
cervical cancer cell lines [5] and in HPV-associated cancers of patients [6]. In
HPV-associated malignant transformation, viral DNA may be integrated into the cellular
DNA and integration often results in deletion of large sectors of the viral genome. Late
genes (L1 and L2) and some early genes (E1 and E2) are usually lost, leaving E6 and E7 as
the only open reading frames frequently found in carcinomas. Expression of E6 and E7 is
likely to overcome the regulation of cell proliferation normally mediated by proteins
like p53 and Rb, allowing uncontrolled growth and providing the potential for malignant
transformation [7].
HPV Oncogenic Proteins, E6 and E7, as Ideal Targets for the Development of
Antigen-Specific Immunotherapies or Vaccines for HPV-Associated Cervical Malignancies E6
and E7 represent ideal targets for the development of antigen-specific immunotherapies or
vaccines for HPV-associated malignancies. First, more than 90% of cervical cancers have
been associated with HPVs, particularly type 16, and E6 and E7 are consistently expressed
in most cervical cancers. Second, while most tumor specific antigens are derived from
normal proteins or mutated protein, E6 and E7 are completely foreign viral proteins, and
potentially may harbor more antigenic peptides/epitopes than a mutant protein (i.e. p53)
or a reactivated embryonic protein (i.e. MAGE-1). Third, since E6 and E7 are required for
the induction and maintenance of malignant phenotype of cancer cells [8], cells of
cervical cancer cannot evade an immune response through antigen loss. Without functional
E6 and E7, these cells would cease to be tumorigenic. Therefore, E6 and E7 proteins
represent ideal targets for developing antigen-specific immunotherapies or vaccines for
cervical cancer.
Various forms of vaccines, such as vector-based vaccines, tumor-based vaccines, DNA based
vaccines and protein/peptide-based vaccines have been described in experimental systems
targeting HPV-16 E6 and/or E7 proteins [9, 10]. For example, Meneguzzi et al. reported
that inoculation of rats with vaccinia recombinants expressing HPV-16 E6 or E7 retarded
or prevented tumor development in 25-47% of rats challenged with a tumorigenic rat cell
line co-transfected with HPV-16 and activated ras [9]. In addition, Chen et al.
demonstrated that immunization of mice with syngeneic non-tumorigenic cells transfected
with the HPV-16 E7 gene confers protection against transplanted HPV-16 E7 positive
syngeneic tumor cells [11]. Feltkamp et al. identified a CTL epitope in HPV-16 E7 using
H-2Kb and H-2Db MHC class I-peptide-binding studies. Immunization with this peptide
rendered mice resistant to a challenge with HPV-16 transformed tumor cells [12].
Furthermore, chimeric papillomavirus-like particles (CVLPs) consist of HPV-16 L1-E7
(Nieland et al., personal communication) or HPV-16 L1/L2-E7 (Greenstone et al., personal
communication) chimeric proteins has been used as therapeutic vaccines against HPV-16 E7
expressing tumors in murine models. More recently, a phase I/II clinical trial were
performed in eight patients with late stage cervical cancer using a live recombinant
vaccinia virus expressing the E6 and E7 proteins of HPV 16 and 18 (TA-HPV) [13]. In that
study, no significant clinical side-effects or environmental contamination by live TA-HPV
were observed [13].
Importance of Cell Mediated Immune Responses in Controlling both HPV Infections and
HPV-Associated Neoplasms Several lines of evidence suggest that cell mediated immune
responses are important in controlling both HPV infections and HPV-associated neoplasms
(for review, see [14]). First, the prevalence of HPV-related diseases (infections and
neoplasms) is increased in transplant recipients [15] and human immunodeficiency virus
(HIV) infected patients [16], both of whom are known to have impaired cell mediated
immunity. Second, animal studies have demonstrated that immunized animals are protected
from papillomavirus infection and from the development of neoplasia. Immunization also
facilitates the regression of existing lesions [17-19]. Third, infiltrating CD4+ (T
helper cells) and CD8+ (cytotoxic /suppressor T cells) T cells have been observed in
spontaneously regressing warts [20] and fourth, warts in patients who are on
immunosuppressive therapy often disappear when this treatment is discontinued (for
review, see [21].
Cellular Immune Responses to HPV The understanding of T-cell mediated immunity to HPV
infections was facilitated by identification of MHC class I and class II epitopes of HPV
proteins. Several groups have attempted to map murine [22-24] and human [25, 26] T helper
(Th) cell epitopes on HPV proteins. Several groups have also tried to map murine [12,
27-30] as well as human [31-34] cytotoxic T-lymphocyte (CTL) epitopes on HPV proteins.
Kast et al. have identified several high affinity binding peptides of HPV-16 E6 and E7
proteins for human HLA-A alleles [32]. Furthermore, HPV-specific CTLs recognizing HPV E6
and E7 proteins have been demonstrated in peripheral blood of cervical cancer patients
[13, 35], in healthy donors [33, 36] and in patients with CIN lesions [34, 37, 38].
Furthermore, infiltration of cervical cancer tissue with HPV-specific CTLs has been
recently described[39].
Cell-mediated immune responses in HPV-infected lesions can be demonstrated by in vivo
skin tests [40, 41], in vitro CTL assays [35, 37, 39] and in vitro lymphoproliferative
response [25, 26, 42-48]. For instance, Hopfl et al. have used bacterially-expressed
HPV-16 proteins for skin tests in patients with CIN lesions and have found specific skin
responses to the virion protein L1 and not the E4 protein [40]. In patients with CIN
lesions, HPV-specific CTLs have been identified in PBMC [35, 37] and in cervical tissues
[39]. The in vitro lymphoproliferative responses in patients with CIN lesions has been
actively investigated. For example, de Gruijl et al. reported that T cell proliferative
responses against HPV-16 E7 oncogenic protein were most prominent in CIN patients with a
persistent HPV infection [45]. However, Kadish et al. reported that lymphoproliferative
responses to specific HPV-16 E6 and E7 peptides appeared to be associated with the
clearance of HPV infection and the regression of CIN lesions [46].
Importance of Helper T Cell Functions in Generating Effective Antitumor Responses
Increasing evidence has suggested that inadequate antitumor responses can result from a
failure of the helper arm of the immune response. The events leading to the activation of
CTL are tightly regulated in order to protect against the development of inappropriate
immune responses to self antigens or exaggerated responses to foreign antigens. This
regulation is mediated by lymphokines produced by CD4+ T helper cells. CD4+ T helper
cells are critical to the generation of potent antitumor immune responses. CD4+ T cells
have been shown to be instrumental in generating immune responses against several solid
malignancies in murine [49, 50] and in human [51, 52]. Several mouse tumors that are
transfected with syngeneic MHC class II genes become very effective vaccines against
subsequent challenge with wild type class II negative tumors [53, 54]. In addition, as
crucial memory cells in the T cell arm of the immune system, CD4+ cells may be able to
provide long term immunity against specific antigens [55, 56].
Role of Cytokines in Cell-Mediated Immunity Cell mediated immunity is regulated by
cytokines which are secreted by T helper cells. In general, T helper cells can be
classified as Th1 and/or Th2 cells based on the different types of cytokines they
secrete. Th1 cells secrete interleukin (IL) 2 and interferon gamma (IFN-). Th2 cells
produce IL-4, IL-5, IL-10 and IL-13. The Th1 lymphocytes are the most important effector
cells in inflammatory reactions associated with vigorous delay-type hypersensitivity but
low antibody production, as occurs in contact dermatitis and in viral or intracellular
bacterial infections (for review, see [57, 58]). The functional phenotype of most Th2
cells may account for both the persistent production of certain antibody isotypes,
particularly IgG1 and IgE, and the eosinophilia observed in human helminthic infections
and allergic disorders. Lymphocyte mediated protection from viral infections as well as
control of tumors is thought to be mediated by Th1 cytokine responses and impaired by Th2
cytokine responses. The IL-2 and IFN- producing Th1 response is likely to be the major
component that contributes to the development of cell mediated immunity against HPV
infections and HPV-associated neoplasms.
Chimeric E7-specific vaccines can control the HPV16 E7-expressing tumor model With
cooperating with Prof. TC Wu in Johns Hopkins Medical Institutes, we have successfully
developed several chimeric DNA, RNA, and virus-vector vaccines to prevent and treat HPV16
E7-expressing tumor in the animal model [59-61]. We found that these E7-chimeric DNA
vaccines are capable of preventing and treating the growth of murine model tumors
expressing E7. These positive results from the preclinical murine models have encouraged
us to focus on the development of cancer vaccine and immunotherapy and apply these
vaccines to human subjects.
However, it is very important to set up various E7-specific immunologic assays of human
being to evaluate the effect of cancer vaccine or immunotherapy in the future clinical
trials. So we would like to provide this proposal to address on the development of HPV 16
E7-specific immunologic assays in human being. There are several aims in this project: 1)
to develop and utilize assays to measure CTLs to HPV 16 E7 proteins, 2) to develop and
utilize assays to measure T helper (Th) responses to HPV 16 E7 antigens.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
normal volunteer, patients with CIN lesions or cervical cancers whose HLA haplotype is
not HLA-A2
Gender:
Female
Minimum age:
18 Years
Maximum age:
80 Years
Healthy volunteers:
Accepts Healthy Volunteers
Locations:
Facility:
Name:
National Taiwan University Hospital
Address:
City:
Taipei
Country:
Taiwan
Status:
Recruiting
Contact:
Last name:
Wen-Fang Cheng, MD, PhD
Phone:
886-2-2312-3456
Phone ext:
5166
Email:
wenfangcheng@yahoo.com
Start date:
January 2002
Completion date:
December 2006
Lead sponsor:
Agency:
National Taiwan University Hospital
Agency class:
Other
Source:
National Taiwan University Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT00155792
