Patient case: 86-year-old female with melanoma; genetic feature: high tumor mutational burden

Clinical trial: Gene-Modified Lymphocytes, High-Dose Aldesleukin, and Vaccine Therapy in Treating Patients With Progressive or Recurrent Metastatic Cancer

Summary: 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 cells.
  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.

Detailed description: OBJECTIVES:
  Primary
  -  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 overexpresses p53.
  Secondary
  -  Determine the in vivo survival of T-cell receptor (TCR) gene-engineered cells.
  -  Determine the ability of a dendritic cell (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 intravenously (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 (growth colony stimulating factor (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.

Eligibility: DISEASE CHARACTERISTICS:
  -  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
  -  Human leukocyte antigens 0201 (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 aldesleukin
  -  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)
  PATIENT CHARACTERISTICS:
  -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  -  Life expectancy > 3 months
  -  Absolute neutrophil count > 1,000/mm^3
  -  White blood cell (WBC) > 3,000/mm^3
  -  Platelet count > 100,000/mm^3
  -  Hemoglobin > 8.0 g/dL
  -  Serum alanine aminotransferase (ALT)/aspartate aminotransferase (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
  -  Human immunodeficiency virus (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 this study
  -  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
  -  Left ventricular ejection fraction (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
  -  Forced expiratory volume 1 (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

Relevance to patient case: not relevant