Group A: Patients have cervical cancer stage IV, recurrent disease, or stage III disease that did not receive appropriate radiation therapy, and patients with other advanced tumors which harbor HPV such as anogenital, esophageal or head and neck cancers. A total of 12 patients will be accrued, 6 patients receive vaccination with HPV16 E6 and the other 6 receive HPV16 E7 peptides.

Group B: Patients have stage III cervical carcinomas that have been treated with standard therapy with no evidence of residual disease. Vaccination in this group is given as an adjuvant therapy. A total of 12 patients will be accrued, 6 patients receive vaccination with HPV16 E6 and the other 6 receive HPV16 E7 peptides.

Patients in Group A and Group B are assigned to either E6 or E7 by the Principal Investigator.

The following acronyms are used:

APC Antigen-Presenting Cells

HPV16 Human Papillomavirus 16

PBMC Peripheral Blood Mononuclear Cells

Vaccine Therapy. Vaccination with autologous APC (PBMC pulsed in vitro with HPV16 E6 or E7 peptide).

Condition	Treatment or Intervention	Phase
Anus Neoplasm Cervix Neoplasm Esophageal Neoplasm Head and Neck Neoplasm Papovaviridae Infection	Drug: E6 peptides  Drug: E7 peptides	Phase I

Further Study Details: 

Expected Total Enrollment:  46

HPV genes and their protein products have been identified in most cervical as well as other anogenital carcinomas. More than 90% of human cervical carcinomas harbor high risk HPV DNA most of which are HPV 16 and 18. The product of the early genes E6 and E7 open reading frames of these viruses have been implicated in the transformation of cervical cancer and are considered the oncogenic products of the HPV DNA genome. Endogenous proteins in the cell, whether of self (e.g. oncoproteins) or foreign (e.g. viral proteins) origin, are degraded in the cells. Fragments of these degraded proteins are presented as small peptides bound to the major histocompatibility complex (MHC) class I molecules on the surface of the cells. These peptides are potentially immunogenic for T lymphocytes.

It has been shown that immunizing mice with nontumorigenic APC's transfected with the HPV16-E7 gene conferred protection against transplanted syngeneic tumor cells expressing HPV16-E7. This protection was mediated by CD8+ lymphocytes. Regression of transplanted tumor expressing HPV16-E6 has also been demonstrated after immunizing mice with syngeneic fibroblast expressing HPV16-E6 protein, and this immunologic response was also shown to be mediated through CTLs. Also, HPV16-E7 peptide was shown to bind with high affinity to the mouse H-2D(b) MHC I molecule. After vaccination, mice were rendered insensitive to subsequent challenge with HPV16-transformed tumor cells. Thus, HPV E6 and E7 proteins can serve as tumor antigens for CTLs which can lyse tumor cells. These CTLs can be generated in vivo by vaccination of mice with synthetic peptides that are able to bind MHC class I molecules.

Therefore, in the present study we propose to test whether HPV E6 and E7 proteins are processed and presented in human tumors for T cell recognition, and if they can therefore be targets for specific peptide vaccination.

Genders Eligible for Study:  Female

Criteria

INCLUSION CRITERIA:
Histologic diagnosis of squamous cell carcinoma of the cervix.
The patient should have stage III, IV, or recurrent disease.
Tumor tissue availability for the determination of the presence of the HPV genome and its type (paraffin block, or fresh tissue).
The tumors should harbor the genome of HPV16.
The patient should be HLA-A2.1 subtype.
It is preferable to have tumor tissue available for preparation of a tumor cell line, and tumor or lymph node tissue for expansion of tumor infiltrating lymphocytes (TIL) for in vitro immunologic laboratory studies. If fresh tissue is not available the patient may be requested to undergo a biopsy procedure if his/her medical status allows the procedure to be performed with minimal risk.
The patient should not have received chemotherapy, radiation therapy, immunotherapy, or steroids for at least 4 weeks prior to starting vaccination. The patient should have recovered from all acute toxicities of previous treatment.
Patients should be more than 18 years old.
ECOG performance status of 0 or 1.
The patient should be able to give an informed consent.
Life expectancy greater than 3 months.
While measurable disease is preferable, in stage IV and recurrent disease, it is not a necessity.
All patients must have a signed informed consent, registered through Orkand before entering on the study.
An adequate T cell response to an HLA-A2 Flu peptide. We define adequate response as either 2 fold increase of IFN gamma response over control (unpulsed target cells), or and increase of 10 % specific lysis over control.
EXCLUSION CRITERIA:
Any condition inconsistent with the inclusion criteria.
HIV infection.
Pregnancy or nursing. Patient with reproductive potential must have a negative pregnancy test. Patient of reproductive age should use adequate contraception.
Any of the following: WBC less than 2000. Lymphocytes less than 800, Platelets less than 100K; Creatinine greater than 2.0 mg/dl; Serum Bilirubin greater than 2.0 mg/dl, SGPT greater than 4 times normal.
Active second malignancy other than basal cell carcinoma of the skin.
History of CNS metastasis.
Active ischemic heart disease (i.e. Class III or VI cardiac disease-New York Heart Association), or a recent history of myocardial infarction (within the last 6 months).
Unresponsiveness to skin test antigens including all the following PPD, Mumps Tricophyton, Candida and Tetanus.
Autoimmune disease e.g., SLE, MS, ankylosing spondylitis, etc.
Active infection requiring antibiotics.
Patients requiring steroids.
Weight loss of greater than 20% of prediagnosis body weight.

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States

Study ID Numbers:  950154; 95-C-0154
Record last reviewed:  June 1, 2004
Last Updated:  November 23, 2004
Record first received:  November 3, 1999
ClinicalTrials.gov Identifier:  NCT00001441
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08