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

National Institutes of Health Clinical Center (CC)

Status and phase: Terminated; Phase 2

Conditions: Unspecified Adult Solid Tumor, Protocol Specific; Melanoma (Skin); Kidney Cancer

Treatments: Biological: autologous dendritic cell-adenovirus p53 vaccine; Drug: fludarabine phosphate; Biological: anti-p53 T-cell receptor-transduced peripheral blood lymphocytes; Biological: aldesleukin; Biological: filgrastim; Drug: cyclophosphamide

Study type: Interventional

Funder types: NIH

Identifiers

NCT00704938

NCI-P07215

080155

NCI-08-C-0155

Details and patient eligibility

About

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.

Full 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.

Enrollment: 3 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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3 participants in 2 patient groups

anti-p53 TCR PBL + DC + IL-2: Melanoma/RCC

Experimental group

Description:

Patients with melanoma and renal cell cancer will receive anti-p53 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + dendritic cells (DC) + interleukin-2 (IL-2)

Treatment:

Drug: cyclophosphamide

Biological: autologous dendritic cell-adenovirus p53 vaccine

Biological: filgrastim

Biological: aldesleukin

Biological: anti-p53 T-cell receptor-transduced peripheral blood lymphocytes

Drug: fludarabine phosphate

anti-p53 TCR PBL + DC + IL-2: Other histology

Experimental group

Description:

Patients with other histologies, such as breast cancer, will receive anti-p53 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + dendritic cells (DC) + interleukin-2 (IL-2)

Treatment:

Drug: cyclophosphamide

Biological: autologous dendritic cell-adenovirus p53 vaccine

Biological: filgrastim

Biological: aldesleukin

Biological: anti-p53 T-cell receptor-transduced peripheral blood lymphocytes

Drug: fludarabine phosphate