T Cell Receptor Immunotherapy Targeting MAGE-A3 for Patients With Metastatic Cancer Who Are HLA-DP0401 Positive
Condition: Cervical Cancer; Renal Cancer; Urothelial Cancer; Melanoma; Breast Cancer
MeSH terms: Neoplasm Metastasis; Kidney Neoplasms
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

      The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for
      treating patients with metastatic cancer that involves taking white blood cells from the
      patient, growing them in the laboratory in large numbers, genetically modifying these
      specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then
      giving the cells back to the patient. This type of therapy is called gene transfer. In this
      protocol, we are modifying the patient s white blood cells with a retrovirus that has the
      gene for anti-Melanoma antigen family A, 3 (MAGE-A3)-DP0401/0402 incorporated in the
      retrovirus.

      Objective:

      The purpose of this study is to determine a safe number of these cells to infuse and to see
      if these particular tumor-fighting cells (anti-MAGE-A3-DP0401/0402 cells) cause tumors to
      shrink and to be certain the treatment is safe.

      Eligibility:

      - Adult's age 18-70 with metastatic cancer expressing the MAGE-A3 molecule.

      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-MAGE-A3-DP0401/0402
           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-MAGE-A3-DP0401/0402 cells and aldesleukin.
           They will stay in the hospital for approximately 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.
    

Detailed description: 
      Background:

        -  We have constructed a single retroviral vector that contains both and $ <= chains of a T
           cell receptor (TCR) that recognizes the DP0401/0402 restricted Melanoma antigen family
           A, 3 (MAGE-A3) tumor antigen, which can be used to mediate genetic transfer of this TCR
           with high efficiency.

        -  In co-cultures with HLA-DP0401/0402 and MAGE-A3 double positive tumors, the anti-
           MAGE-A3- DP0401/0402 restricted (anti-MAGE-A3-DP4) TCR transduced T cells secreted
           significant amounts of Interferon gamma (IFN-y) with high specificity.

      Objectives:

      Primary objectives:

        -  Determine a safe dose of the administration of autologous cluster of differentiation 4
           (CD4) cells transduced with an anti-MAGE-A3-DP0401/0402 restricted (MAGE-A3-DP4) TCR and
           aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative
           regimen.

        -  Determine if this approach will result in objective tumor regression in patients with
           metastatic cancer expressing MAGE-A3-DP4.

        -  Determine the toxicity profile of this treatment regimen.

      Eligibility:

      Patients who are human leukocyte antigens (HLA)-DP0401/0402 positive and 18 years of age or
      older must have

        -  Metastatic cancer whose tumors express the MAGE-A3-DP4 antigen.

        -  Previously received and have been a non-responder to or recurred following at least one
           first line treatment for metastatic disease.

      Patients may not have:

      - Contraindications for high dose aldesleukin administration.

      Design:

        -  PBMC obtained by leukapheresis will be enriched for CD4 cells and transduced with the
           retroviral vector supernatant encoding the anti-MAGE-A3-DP4 TCR.

        -  The study will begin in a standard phase 1 dose escalation. After the maximum tolerated
           dose (MTD) cell dose has been determined, patients will be enrolled into the phase 2
           portion of the trial at the MTD established during the phase 1 portion of the study. In
           the phase 2 portion, patients will be entered into two cohorts: cohort 1 will include
           patients with metastatic melanoma; cohort 2 will include patients with renal cancer and
           other types of metastatic cancer.

        -  Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen
           consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex
           vivo tumor reactive, TCR gene-transduced peripheral blood mononuclear cells (PBMC) plus
           intravenous (IV) aldesleukin.

        -  Patients will undergo complete evaluation of tumor response every 1-6 months until off
           study criteria are met.

        -  For each of the 2 strata evaluated in the phase 2 portion, the study will be conducted
           using a phase 2 optimal design where initially 21 evaluable patients will be enrolled.
           For each of these two arms of the trial, if 0 or 1 of the 21 patients experiences a
           clinical response, then no further patients will be enrolled but if 2 or more of the
           first 21 evaluable patients enrolled have a clinical response, then accrual will
           continue until a total of 41 evaluable patients have been enrolled in that stratum.

        -  For both strata, the objective will be to determine if the treatment regimen 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).
    

Intervention name(s): Anti-MAGE-A3-DP4 T Cell Receptor (TCR) Peripheral Blood Lymphocytes (PBL); Cyclophosphamide; Fludarabine; Aldesleukin
Intervention type(s): Biological; Drug; Drug; Drug
Intervention description(s): Day 0: cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes; Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5 % in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hour.; 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 intravenous (IV) (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) 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
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Gene Therapy; Tumor Regression; Immunotherapy; Adoptive Cell Therapy