Phase II Study of Metastatic Cancer That Overexpresses P53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-P53 TCR-Gene Engineered Lymphocytes
Condition: Anti-p53 TCR-Gene
MeSH terms: Neoplasm Metastasis
Intervention: anti-protein 53 or tumor protein 53 (p53) T-cell receptor transduced peripheral blood lymphocytes; aldesleukin; filgrastim; cyclophosphamide; fludarabine phosphate
Intervention description: Peripheral blood lymphocytes are harvested by lymphapheresis and engineered to express a T cell receptor that binds to P53.; 720,000 IU/kg intravenously over 15 minutes every 8 hours for up to 5 days; Beginning on day 1 or 2, administered subcutaneously at a dose of 5 mcg/kg/day (not to exceed 300 mcg/day); continue daily until neutrophil count > 1.0 x 10^9/L x 3 days or > 5.0 x 10^9/L.; 60 mg/kg/day x 2 days intravenously in 250ml dextrose 5% in water (D5W) with mesna 15 mg/kg/day x 2 days over 1 hour.; 25 mg/m2/day intravenously piggyback (IVPB) daily over 30 minutes for 5 days.
Intervention MeSH terms: Aldesleukin; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Interleukin-2; Lenograstim
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Tumor Regression; In Vivo Cell Survival; Toxicity Profile; Metastatic Renal Cell Cancer; Cancer; Metastatic Cancer

Summary:

      Background:

      The p53 gene normally suppresses tumor growth, but when it is mutated, or damaged, tumors can
      grow unchecked.

      In cancers where the p53 gene has mutated, an increased level of p53(overexpression of p53)
      can be measured in the tumor.

      Objectives To determine whether advanced cancers that overexpress p53 can be treated
      effectively with lymphocytes (white blood cells) that have been genetically engineered to
      contain an anti-p53 protein.

      Eligibility Patients 18 years of age and older with metastatic cancer (cancer that has spread
      beyond the original site) Patient's tumor overexpresses p53 Patient's leukocyte antigen type
      is HLA-A 0201 Design

      Patients undergo the following procedures:

      Leukapheresis (on two occasions). This is a method of collecting large numbers of white blood
      cells. The cells obtained in the first leukapheresis procedure are grown in the laboratory,
      and the anti-p53 protein is inserted into the cells using an inactivated (harmless)virus in a
      process called transduction. Cells collected in the second leukapheresis procedure are used
      to evaluate the effectiveness of the study treatment.

      Chemotherapy. Patients are given chemotherapy through a vein (intravenously, IV) for 1 week
      to suppress the immune system so that the patients immune cells do not interfere with the
      treatment.

      Treatment with anti-p53 cells. Patients receive an IV infusion of the transduced cells
      containing anti-p53 protein, followed by infusions of a drug called IL-2, which helps boost
      the effectiveness of the transduced white cells.

      Patients may undergo a tumor biopsy (removal of a small piece of tumor tissue). Patients are
      evaluated with laboratory tests and imaging tests, such as computed tomography (CT) scans 4
      to 6 weeks after treatment and then once a month 3 to 4 months to determine the response to
      treatment.

      Patients have blood tests at 1, 3, 6 and 12 months and then annually for the next 10 years.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have metastatic cancer that overexpresses p53 as assessed by
             immunohistochemistry, as determined by positive staining of tumor sample. when
             compared to negative controls per procedure in Appendix 1. The immunohistochemical
             staining will be performed in the Pathology Laboratory Center for Cancer Research
             (CCR), National Cancer Institute (NCI) on fresh or archival tissue and will be
             supervised by Dr. Maria Merino. The criteria used to determine overexpression will be
             that used in the Laboratory of Dr. Curt Harris. Ten fields will be evaluated at 40 X
             magnification and if greater than 5% of cells stain positive, the tumor will be
             categorized as an overexpressor.

          -  Patients with melanoma or renal cell cancer must have previously received
             interleukin-2 (IL-2) and have been either non-responders (progressive disease) or have
             recurred. Patients with other histologies,not including hematologic malignancies, must
             have previously received first line and second line or higher systemic standard
             care(or effective salvage chemotherapy regimens) for metastatic disease,if known to be
             effective for that disease and have been either non-responders (progressive disease)
             or have recurred.

          -  Age greater than or equal to 18 years.

          -  Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 to 1.

          -  Life expectancy of greater than three months.

          -  Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental
             treatment being evaluated in this protocol depends on an intact immune system.
             Patients who are HIV seropositive can have decreased immune competence and thus be
             less responsive to the experimental and more susceptible to its toxicities).

          -  Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen negative.

          -  Patients must be human leukocyte antigen A(HLA-A) 0201 positive.

          -  Patients of both genders must be willing to practice birth control for four months
             after receiving the preparative regimen.

          -  Absolute neutrophil count greater than 1000/mm^3, and normal white blood cells (WBC)
             (greater than 3000/mm^3).

          -  Platelet count greater than 100,000/mm^3.

          -  Hemoglobin greater than 8.0 g/dl.

          -  Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than the
             upper limit of normal.

          -  Serum creatinine less than or equal to 1.6 mg/dl.

          -  Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's
             Syndrome who must have a total bilirubin less than 3.0 mg/dl.

          -  More than four weeks must have elapsed since any prior systemic therapy at the time
             the patient receives the preparative regimen, and patients toxicities must have
             recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).
             Six weeks must have elapsed since prior Ipilimumab (MDX-010) therapy to allow antibody
             levels to decline, and patients who have previously received MDX-010 must have a
             normal colonoscopy with normal colonic biopsies.

          -  Women of child-bearing potential must have a negative pregnancy test because of the
             potentially dangerous effects of the preparative chemotherapy on the fetus.

          -  A biopsy must be evaluable to evaluate p53 expression and to confirm the diagnosis by
             the Laboratory of Pathology, CCR, NCI.

        Exclusion Criteria:

          -  Patients requiring systemic steroid therapy

          -  Patients with active systemic infections, coagulation disorders or other major medical
             illnesses of the cardiovascular, respiratory or immune system, myocardial infarction,
             cardiac arrhythmias, obstructive or restrictive pulmonary disease.

          -  Patients with any form of primary immunodeficiency (such as Severe Combined
             Immunodeficiency Disease and acquired immune deficiency syndrome (AIDS)). Patients
             with opportunistic infections will be excluded. (The experimental treatment being
             evaluated in this protocol depends on an intact immune system. Patients who have
             decreased immune competence may be less responsive to the experimental treatment and
             more susceptible to its toxicities).

          -  Patients with history of severe immediate hypersensitivity reaction to any of the
             agents used in this study.

          -  Patient is not willing to sign a durable power of attorney.

          -  Patient is not able to understand and sign the Informed Consent Document.

          -  Since aldesleukin will be excluded if they have a history of electrocardio- gram (EKG)
             abnormalities, symptoms of cardiac ischemia or arrhythmias and have a left ventricular
             ejection fraction (LVEF) less than 45% on a cardiac stress test (stress thallium,
             stress multi-gated acquisition scan (MUGA), dobutamine echocardiogram, or other stress
             test).

          -  Similarly, patients who are greater than or equal to 50 years old with a LVEF less
             than 45% will be excluded.

          -  Patients with a prolonged history of cigarette smoking (greater than 20 pack/year
             within the past 2 years) or symptoms of respiratory dysfunction (e.g. grade 2 dyspnea
             or hypoxia) who do not have a normal pulmonary function test as evidenced by a FEV(1)
             less than 60% predicted will be excluded.