Patient case: 49-year-old male with melanoma; genetic feature: extensive tumor infiltrating lymphocytes

Clinical trial: Cellular Adoptive Immunotherapy Using Autologous CD8+ Antigen-Specific T Cells and Anti-CTLA4

Summary: The goal of this clinical research study is to learn about the safety of giving CD8+T cells with ipilimumab, cyclophosphamide, and IL-2 (aldesleukin). Researchers also want to learn if this combination can help to control metastatic melanoma.
  This study is divided into 2 parts: leukapheresis and treatment. In the leukapheresis part, blood cells will be collected from you to be made into modified CD8+T cells and given back to you in the treatment part.
  CD8+T cells are a type of white blood cell. Researchers grow the T cells in the laboratory, and they are designed to find melanoma cancer cells and may kill them.
  Ipilimumab and aldesleukin are designed to increase the immune system's ability to fight cancer.
  Cyclophosphamide will be used at a very low dose to weaken the body's natural defense against the T-cell transplant, so that the transplanted T-cells have a chance to grow and multiply.

Detailed description: Study Drug Administration:
  If you agree to take part in this study, you will receive cyclophosphamide by vein over about 30-60 minutes on Day -2 (2 days before you receive the CD8+ T cells). If the doctor thinks it is needed, you will be given standard drugs to help decrease the risk of side effects. You may ask the study staff for information about how the drug is given and its risks.
  On Day 0, you will receive the CD8+ T cells by vein over about 30-60 minutes. You will stay in the hospital overnight after the dose.
  Starting within 6 hours after the CD8+T cell infusion and then 2 times a day after that for 14 days, you will give aldesleukin as an injection into your skin around your abdomen. You will be taught how to give yourself these injections.
  On Days 1, 22, 43, and 64, you will receive ipilimumab by vein over about 90 minutes.
  Study Visits:
  On Day -2:
  -  You will have a physical exam.
  -  Blood (about 1 tablespoon) will be drawn for routine tests. This routine blood draw will include a pregnancy test if you can become pregnant. To continue your participation in this study, you cannot be pregnant.
  On Days 0, 7, 14, 22, 28, 35, 43, 49, 56, 64, 70, 77, 84, 112, and 140:
  -  You will have a physical exam.
  -  Blood (about 5½ tablespoons) will be drawn for routine tests, immune system tests, and tests on how long the T-cells survive in your body.
  -  Between Day 35 and 42 and again between Day 77 and 84, you will have a CT scan to check the status of the disease.
  On Day 3, blood (about 5½ tablespoons) will be drawn for routine tests, immune system tests, and tests on how long the T-cells survive in your body.
  If the doctor thinks it is needed to confirm the status of the disease, blood (about 1½ tablespoons) will be drawn every 3-6 months for up to 3 years.
  The study tests may be repeated or you may have additional tests performed anytime the doctor thinks it is needed.
  Some of the study tests may be done at your local clinic if you cannot return to MD Anderson. The study staff will discuss this with you.
  Length of Treatment:
  The treatment portion of the study will last until Day 64. You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.
  Your participation on the study will be over after the follow-up.
  End-of-Study Visit:
  At Day 168:
  -  You will have a physical exam.
  -  Blood (about 5½ tablespoons) will be drawn for routine tests, immune system tests, and tests on how long the T-cells survive in your body.
  Follow-Up:
  Every 3 months after Day 84, unless the disease gets worse or you start another cancer therapy, you will have a CT scan or x-rays to check the status of the disease. Every 3 months for up to 5 years, the study staff will call you or ask your doctor how you are doing. If you are called, the calls should last about 10-15 minutes.
  If the doctor thinks it is needed, you will return to the clinic every 4-6 weeks or as often as the doctor thinks is needed. Blood (about 5½ tablespoons) will be drawn for routine tests, immune system tests, and tests on how long the T-cells survive in your body.
  This is an investigational study. CD8+T cells are not FDA approved or commercially available. They are currently being used for research purposes only. Cyclophosphamide, ipilimumab, and aldesleukin are FDA approved and commercially available for the way they are being used in this study.
  Up to 30 participants will be enrolled in this multicenter study. Up to 20 will take part at MD Anderson.

Eligibility: Inclusion Criteria:
  1. Histopathologic documentation of melanoma concurrent with the diagnosis of metastatic disease.
  2. Male or female subjects >/= 18 years of age.
  3. Expression of HLA-A2.
  4. ECOG/ Zubrod performance status of '0-1' at screening visit.
  5. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized. Suggested precautions should be used to minimize the risk or pregnancy for at least 1 month before start of therapy, and while women are on study for up to 3 months after T cell infusion, and at least 8 weeks after the study drug is stopped. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal.
  6. Men must be willing and able to use an acceptable method of birth control, for at least 3 months after completion of the study, if their sexual partners are WOCBP.
  7. Willing and able to give informed consent.
  8. Adequate venous access - consider PICC or central line.
  9. Evaluation of BRAFV600 mutation status.
  10. Measurable tumor (by RECIST criteria).
  11. MART 1 or SLC45A2 (+) staining results. (If patients have not had staining test in the past, the test will be run after patient consent is obtained, but before enrollment).
  Exclusion Criteria:
  1. Any other malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix.
  2. Pregnant women, nursing mothers, men or women of reproductive ability who are unwilling to use effective contraception. Women of childbearing potential with a positive pregnancy test within 3 days prior to entry.
  3. Active and untreated central nervous system (CNS) metastasis (including metastasis identified during screening MRI or contrast CT). • No signs or symptoms of CNS mets within the last 30 days (from enrollment evaluation). • No single lesion larger than 1cm • No more than 5 lesions
  4. Autoimmune disease: Patients with a history of Inflammatory Bowel Disease are excluded from this study, as are patients with a history of autoimmune disease (e.g. Systemic Lupus Erythematosus, vasculitis, infiltrating lung disease) whose possible progression during treatment would be considered by the Investigator to be unacceptable.
  5. Any underlying medical or psychiatric condition, which in the opinion of the Investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea.
  6. Positive screening tests for HIV, Hep B, and Hep C (referencing blood draw at leukapheresis screening). If positive results are not indicative of true active or chronic infection, the patient can be treated.
  7. CBC and Chemistry profile prior to cyclophosphamide and T cell infusions: •WBC </= 1000/uL •Hct </= 24% or Hemoglobin </=8 g/dL •ANC </= 500 •Platelets </= 50,000 •Creatinine >/= 3.0 x ULN •AST/ALT >/= 2.5 x ULN, •Bilirubin >/= 3 x ULN
  8. Steroids are not permitted 3 days prior to T cell infusion and concurrently during therapy.
  9. Any non-oncology vaccine therapy used for the prevention of infectious disease within 1 month before or after any ipilimumab dose.
  10. Patients may not be on any other treatments for their cancer aside from those included in the protocol. Patients may not undergo another form of treatment concurrently with this study.
  11. Pregnant women, nursing mothers, men or women of reproductive ability who are unwilling to use effective contraception. Women of childbearing potential with a positive pregnancy test within 3 days prior to entry.

Relevance to patient case: not relevant