This study will examine whether vaccination with a p53 peptide can boost an immune response
to ovarian cancer and what the side effects are of the vaccine.
Many patients with ovarian cancer have an altered (mutated) gene called p53 that causes the
production of abnormal proteins found in their tumor cells. The body s immune system may try,
unsuccessfully, to fight these abnormal proteins. In this study, ovarian cancer patients with
a p53 abnormality will be vaccinated with a p53 peptide a part of the same abnormal protein
found in their tumor to try to boost their body s immune response to the cancer.
Patients will be divided into two groups. Group A will have four p53 peptide vaccinations
three weeks apart, injected under the skin. The injection will include a drug called ISA-51,
which increases the effect of the vaccine. This group will also receive two other drugs that
boost the immune system, IL-2 and GM-CSF. Group B will have four p53 peptide vaccinations
three weeks apart. The peptide will be mixed with the patient s own blood cells and infused
into a vein. This group will also receive IL-2, but not GM-CSF.
All study candidates will be tested to see if their cancer has a p53 abnormality and if their
immune system mounted a defense against it. These tests may include a tumor biopsy (removal
of a small part of the tumor for microscopic examination); lymphapheresis (a procedure to
take blood, remove white blood cells called lymphocytes, and return the red cells); and an
immune response test similar to a skin test for tuberculosis. During the study, patients will
have additional skin tests and blood tests.
P53 is the most commonly mutated gene in human cancers; it has been found to be mutated in
almost 50% of ovarian cancers. Genetic mutation of p53 results in stabilization and increase
in the level of the protein. In some cases, overexpression of p53 protein could also occur in
tumors without detectable mutation in the open reading frame. Therefore, p53 could function
as an antigen through two different mechanisms, as a mutant "foreign" protein and as a
selfoverexpressed protein. The p53:264 - 272 wild type peptide has been shown to have high
affinity for HLA-A2. It has also been shown to be naturally processed and endogenously
presented by HLA-A2 in different types of tumor cell lines for CTL recognition. These CTL
were able to lyse tumor cells overexpressing wild type or mutant p53 protein and failed to
normal cells expressing normal levels of wild type p53.
In this protocol we will be vaccinating HLA-A2+ ovarian cancer patients who carry tumors
which overexpress p53 with the wild type p53 peptide (264-272). This will be given either
subcutaneously admixed with ISA-51 and GM-CSF adjuvants, or intravenously pulsed on dendritic
cells along with low dose subcutaneous IL-2. In addition, those patients who express mutant
p53 may also be vaccinated with a mutant p53 peptide, which corresponds to the mutation they
harbor in their tumor, should the patients progress on the p53 (264-272) peptide.
- INCLUSION CRITERIA:
Patients must be 18 years of age or older.
Histologic diagnosis of adenocarcinoma of the ovary.
Tumor tissue availability for determination of p53 protein expression and genetic mutation
(paraffin block, or fresh tissue).
Immunohistochemical analysis of the tumor must demonstrate positive p53 staining.
Patients should have ovarian cancer with marker only disease or patients with stage III, IV
or recurrent who are NED post therapy.
ECOG performance status of 1 or 0.
Expected survival of more than 3 months.
The patients should not have received chemotherapy, radiation therapy, immunotherapy or
systemic doses of steroids for at least 4 weeks prior to starting vaccination. And the
patient should have recovered from all acute toxicities of previous treatment. Patients who
received bone marrow transplantation within a year will not be eligible for the trial.
Patients must understand and sign an informed consent document that explains the neoplastic
nature of his/her disease, the procedures to be followed, the experimental nature of the
treatment, alternative treatments, and potential risks and toxicities.
Patients should have HLA-A2.1 haplotype.
Any condition that does not fit with the eligibility criteria.
Any of the following:
Platelets less than 100K/mm(3)
Creatinine greater than 2.0 mg/dl
Serum Bilirubin greater than 2.0 mg/dl, SGOT, or SGPT greater than 4 times normal
HIV or Hepatitis B or C (i.e. detectable HBS Antigen or HC Ab) since these conditions might
have an effect on the immune system.
Pregnant women or nursing mothers are ineligible since the effect of this investigational
treatment on the health of the embryo is not known. Women with reproductive potential must
have negative pregnancy test and must use adequate contraception.
Patients with active ischemic heart disease (i.e. Class III or IV cardiac disease-New York
Heart Association), a recent history of myocardial infarction (within the last 6 months),
history of congestive heart failure, ventricular arrythmias or other arrythmias requiring
Second malignancy (within the past 2 years) other than curatively treated carcinoma in-situ
of cervix or basal cell carcinoma of the skin. These patients will be excluded for the
possibility of the existence of a different mutation in the other primary malignancy.
History of CNS metastases.
Patients with underlying immune deficiency or history of autoimmune disease e.g.
(autoimmune neutropenia, thrombocytopenia, or hemolytic anemia; systemic lupus
erythematosus, Sjogren syndrome, or scleroderma; myasthenia gravis; Goodpasture syndrome;
Addison's disease, Hashimoto's thyroiditis, active Graves' disease, or other diseases which
qualify as autoimmune in origin).
Patients with active infections requiring antibiotics. Patients requiring chronic
suppressive antibiotics will be eligible for the trial.
If, in the opinion of the principal or associate investigators, it is not in the best
medical interest of the patient to enter this study, the patient will be ineligible.