T Cell Receptor Immunotherapy Targeting NY-ESO-1 for Patients With NY-ESO-1 Expressing Cancer
Condition: Melanoma; Meningioma; Breast Cancer; Non-Small Cell Lung Cancer; Hepatocellular Cancer
MeSH terms: Melanoma; Meningioma; Liver Neoplasms; Carcinoma, Hepatocellular
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

      The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for
      treating patients with cancer that involves taking white blood cells from the patient,
      growing them in the laboratory in large numbers, genetically modifying them, and then giving
      the cells back to the patient. In a previous study the NCI Surgery Branch used the anti-ESO-1
      gene and a type of virus (retrovirus) to make these tumor fighting cells (anti-ESO-1 cells).
      About half of the patients who received this treatment experienced shrinking of their tumors.
      In this study, we are using a slightly different method of producing the anti-ESO-1 cells
      which we hope will be better in making the tumors shrink.

      Objectives:

      The purpose of this study is to see if these tumor fighting cells (genetically modified
      cells) that express the receptor for the ESO-1 molecule on their surface can cause tumors to
      shrink and to see if this treatment is safe.

      Eligibility:

      - Patients 15 years old and older with cancer that has the ESO-1 molecule on their tumors.

      Design:

        -  Work up stage: Patients will be seen as an outpatient at the National Institutes of
           Health (NIH) clinical Center and undergo a history and physical examination, scans,
           x-rays, lab tests, and other tests as needed

        -  Leukapheresis: If the patients meet all of the requirements for the study they will
           undergo leukapheresis to obtain white blood cells to make the anti ESO-1 cells.
           {Leukapheresis is a common procedure which removes only the white blood cells from the
           patient.}

        -  Treatment: Once their cells have grown the patients will be admitted to the hospital for
           the conditioning chemotherapy, the anti-ESO-1 cells and aldesleukin. They will stay in
           the hospital for about 4 weeks for the treatment.

        -  Follow up: Patients will return to the clinic for a physical exam, review of side
           effects, lab tests, and scans about every 1-3 months for the first year, and then every
           6 months to 1 year as long as their tumors are shrinking. Follow up visits take up to 2
           days.
    

Detailed description: 
      PRECIS

      Background:

        -  We have constructed a single retroviral vector that contains both and <= chains of a
           murine T cell receptor (mTCR) that recognizes the New York Esophageal Squamous Cell
           Carcinoma-1 (NY-ESO-1) (ESO) tumor antigen, which can be used to mediate genetic
           transfer of this T-cell receptor (TCR) with high efficiency.

        -  In co-cultures with human leukocyte antigen serotype within the HLA-A serotype group
           (HLA-A2) and ESO double positive tumors, anti-ESO mTCR transduced T cells secreted
           significant amounts of Interferons (IFN)- >= with high specificity.

      Primary objective:

      - To determine whether the administration of anti-ESO mTCR-engineered peripheral blood
      lymphocytes (PBL) plus high-dose aldesleukin following a non-myeloablative lymphoid depleting
      preparative regimen may result in objective tumor regression in patients with metastatic
      cancers including melanoma expressing the ESO antigen.

      Eligibility:

        -  Age greater than or equal to 15 years and less than or equal to 70 years. Patients aged
           15-17 years must weigh at least 50 kg.

        -  HLA-A*0201 positive

        -  Metastatic cancer including melanoma whose tumors express the ESO antigen

        -  Previously received and have been a non-responder to or recurred after receiving
           standard care for metastatic disease

        -  No contraindications for high-dose aldesleukin administration

      Design:

        -  Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis will be cultured in
           the presence of anti-CD3 monoclonal antibody (OKT3) and aldesleukin to stimulate T-cell
           growth.

        -  Transduction is initiated by exposure of cells to retroviral vector supernatant
           containing the anti-ESO mTCR genes. This mTCR targets the exact same epitope as the
           human T-cell receptor (hTCR).

        -  All patients will receive a non-myeloablative lymphocyte depleting preparative regimen
           of cyclophosphamide and fludarabine.

        -  On day 0 patients will receive anti-ESO mTCR gene-transduced PBMC and then begin high
           dose aldesleukin.

        -  A complete evaluation of evaluable lesions will be conducted 6 weeks (+/- 2 weeks)
           following the administration of the cell product.

        -  The study will be conducted using a phase II optimal design (Simon R, Controlled
           Clinical Trials 10:1-10, 1989). The objective will be to determine if the combination of
           high dose aldesleukin, lymphocyte depleting chemotherapy, and anti-ESO TCR-gene
           engineered lymphocytes is able to be associated with a clinical response rate that can
           rule out 5% (p0=0.05) in favor of a modest 20% Partial Response (PR) + Complete Response
           (CR) rate (p1=0.20).

        -  A total of up to 43 patients may be enrolled (41, plus allowing for up to 2
           non-evaluable patients).
    

Intervention name(s): Anti-NY ESO-1 mTCR PBL; Cyclophosphamide; Fludarabine; Aldesleukin
Intervention type(s): Biological; Drug; Drug; Drug
Intervention description(s): Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20-30 minutes.; Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days intravenously (IV) in 250 mL dextrose 5% in water (D5W) infused simultaneously with mesna 15 mg/kg/day over 1 hour x 2 days.; Days -7 to -3: Fludarabine 25 mg /m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.; Aldesleukin 720,000 IU/kg intravenously (IV) (based on total body weight) over 15 minutes every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).
Other intervention name(s): Cytoxan; Fludara; Proleukin
Intervention MeSH terms: Aldesleukin; Cyclophosphamide; Fludarabine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Metastatic Cancer; Gene Therapy; Immunotherapy; Tumor Regression; Melanoma