RATIONALE: Gene-modified lymphocytes may stimulate the immune system in different ways and
stop tumor cells from growing. High-dose aldesleukin may stimulate lymphocytes to kill tumor
cells. Vaccines made from a gene modified virus and a person's dendritic cells may help the
body build an effective immune response to kill tumor cells. Giving gene-modified
lymphocytes together with high-dose aldesleukin and vaccine therapy may kill more tumor
PURPOSE: This phase II trial is studying how well giving gene-modified lymphocytes together
with high-dose aldesleukin and vaccine therapy works in treating patients with progressive
or recurrent metastatic cancer.
- Determine if the administration of anti-p53 T-cell receptor (TCR) gene-engineered
peripheral blood lymphocytes, high-dose aldesleukin, and adenovirus p53 dendritic cell
(DC) vaccine after a nonmyeloablative, but lymphoid-depleting, preparative regimen will
result in clinical tumor regression in patients with metastatic cancer that
- Determine the in vivo survival of TCR gene-engineered cells.
- Determine the ability of a DC vaccine to restimulate TCR gene-engineered cells in vivo.
- Determine the toxicity profile of this treatment regimen.
OUTLINE: Patients are stratified according to type of metastatic cancer (melanoma or renal
cell cancer vs all other cancers).
- Peripheral blood mononuclear cell (PBMC) collection: Patients undergo PBMC collection
via leukapheresis for the generation of the adenovirus p53 dendritic cell vaccine as
well as anti-p53 T-cell receptor (TCR) gene-engineered peripheral blood lymphocytes.
- Nonmyeloablative lymphocyte-depleting preparative regimen: Patients receive
cyclophosphamide IV over 1 hour on days -7 and -6 and fludarabine phosphate IV over 30
minutes on days -5 to -1.
- Peripheral blood lymphocyte infusion: Patients receive anti-p53 TCR gene-engineered
peripheral blood lymphocytes IV over 20-30 minutes on day 0. Patients receive
filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day 1 or 2 and
continuing until blood counts recover.
- High-dose aldesleukin: Patients receive high-dose aldesleukin IV over 15 minutes three
times daily on days 0-4 for up to 15 doses.
- Dendritic cell vaccine: Patients receive adenovirus p53 dendritic cell vaccine SC on
days 0, 7, 14, and 28.
Patients may receive one re-treatment course as above (nonmyeloablative preparative regimen,
peripheral blood lymphocyte infusion, high-dose aldesleukin, and dendritic cell
vaccinations) beginning 6-8 weeks after the last dose of high-dose aldesleukin.
After completion of study treatment, patients are followed periodically for up to 15 years.
- Diagnosis of metastatic cancer
- Tumor overexpresses p53 as assessed by immunohistochemistry (i.e., ≥ 5% tumor cells
stain positive for p53)
- Biopsy must be available to evaluate p53 expression
- HLA-A*0201 positive
- Progressive or recurrent disease after prior standard therapy for metastatic disease
- Patients with melanoma or renal cell cancer must have previously received
- Patients with other histologies, not including hematologic malignancies, must
have previously received first-line and second-line or higher systemic standard
therapy (or effective salvage chemotherapy regimens)
- ECOG performance status 0 or 1
- Life expectancy > 3 months
- Absolute neutrophil count > 1,000/mm^3
- WBC > 3,000/mm^3
- Platelet count > 100,000/mm^3
- Hemoglobin > 8.0 g/dL
- Serum ALT/AST ≤ 2.5 times upper limit of normal
- Serum creatinine ≤ 1.6 mg/dL
- Total bilirubin ≤ 2.0 mg/dL (< 3.0 mg/dL in patients with Gilbert's syndrome)
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for 4 months after
completion of study treatment
- Patients who have previously received ipilimumab or ticilimumab must have a normal
colonoscopy with normal colonic biopsies
- HIV antibody negative
- Hepatitis B antigen and hepatitis C antibody negative (unless antigen negative)
- No primary immunodeficiency (e.g., severe combined immunodeficiency disease)
- No active systemic infections
- No history of severe immediate hypersensitivity reaction to any of the agents used in
- No coagulation disorders
- No myocardial infarction or cardiac arrhythmias
- No history of coronary revascularization
- No obstructive or restrictive pulmonary disease
- No contraindications for high-dose aldesleukin administration
- LVEF ≥ 45% in patients meeting any of the following criteria:
- History of ischemic heart disease, chest pain, or clinically significant atrial
and/or ventricular arrhythmias including, but not limited to, atrial
fibrillation, ventricular tachycardia, or second- or third-degree heart block
- At least 60 years of age
- FEV_1 > 60% predicted in patients meeting any of the following criteria:
- Prolonged history of cigarette smoking (> 20 pack/year within the past 2 years)
- Symptoms of respiratory dysfunction
- No other major medical illness of the cardiovascular, respiratory, or immune system
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- Recovered from prior therapy
- More than 4 weeks since prior and no concurrent systemic steroid therapy
- More than 4 weeks since other prior systemic therapy
- More than 6 weeks since prior ipilimumab