Patient case: 18-year-old male with anaplastic large cell lymphoma; genetic feature: ALK

Clinical trial: Multi-Dose CD30 CAR T Cells, Relapsed CD30 Expressing Lymphoma (RELY-30)

Summary: The subject has a type of lymph gland cancer called Lymphoma.
  The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancer. This research study combines two different ways of fighting disease: antibodies and T cells. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected with germs. Both antibodies and T cells have been used to treat patients with cancers; they both have shown promise, but have not been strong enough to cure most patients. Investigators hope that both will work better together.
  Investigators have found from previous research that they can put a new gene into T cells that will make them recognize cancer cells and kill them. They now want to test whether multiple doses of these genetically modified T cells will be more effective at killing cancer cells.
  The gene that will be put into the T cells makes an antibody called anti-CD30. This antibody sticks to lymphoma cells because of a substance on the outside of the cells called CD30. Anti-CD30 antibodies have been used to treat people with lymphoma, but have not been strong enough to cure most patients.
  For this study, the anti-CD30 antibody has been changed so that instead of floating free in the blood it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These CD30 chimeric receptor-activated T cells (CD30.CAR T cells) seem to kill some of the tumor, but they don't last very long and so their chances of fighting the cancer are unknown.
  Several studies suggest that the infused T cells need room to be able to multiply and grow to accomplish their functions, and that this may not happen if there are too many other T cells in circulation. Because of that, doctors may use chemotherapy drugs to decrease the level of circulating T cells prior to the CD30.CAR T cells infusion. This is called "lymphodepletion".
  CD30.CAR T cells have previously been studied in lymphoma patients. What is new for this study is that multiple doses of CAR T cells will be administered, and that lymphodepletion chemotherapy will be administered in patients who are not post autologous transplant in the hope that it will result in more durable anti-tumor effects.

Detailed description: To prepare the CD30.CAR T cells, research staff will take some blood from the subject. This would be drawn as 2 (two) separate blood collections.
  Alternatively, if the subject's blood counts are low, staff may collect the cells needed to prepare T cells by a pheresis procedure. This procedure will involve placing a needle in both arms, collecting the cells over 3 to 6 hours during which the subject will be required to lie relatively still.
  After the T cells have been collected, some of them will be activated stimulating them with antibodies and will then be infected with a retroviral vector (a special virus that can carries a new gene into cells) containing a new gene called anti-CD30 that will make an antibody to lymphoma cells. The trained cells are called CD30.CAR T cells. Then, the cells will be tested to make sure that they kill lymphoma cells that express the CD30 antigen and not normal cells.
  The cells generated will be frozen and stored to give back to the subject.
  This is a dose escalation study. This means that at the beginning, patients will be started on the lowest doses (1 of 3 different levels) of CD30.CAR T Cells. Once that dose schedule proves safe, the next group of patients will be started at a higher dose. This process will continue until all 3 dose levels are studied. If the side effects are too severe, the dose will be lowered or the T cell infusions will be stopped. The risks of harm and discomfort from the study treatment may bear some relationship to the dose level. The potential for direct benefit, if any, may also vary with the dose level.
  Subjects will be given two injections of CD30.CAR T cells. The first injection will be on Day 0 and the second injection will be given two weeks later on Day 14. The CD30.CAR T cells will be injected into the vein through an IV line at the assigned dose. The injection will take 1-10 minutes.
  If the subject is not post autologous transplant they will receive treatment with cyclophosphamide and fludarabine (chemotherapy drugs) before the CD30.CAR T cells. These drugs will decrease the numbers of the patient's T cells before the CD30.CAR T cells are infused. Although the investigators do not expect any effect on the tumor with the dose that the patient will receive, these drugs are part of many regimens that are used to treat lymphoma or leukemia.
  In between the first and second T cell infusions and for 6 weeks after the last infusion, investigators ask that subjects not receive any other anti-cancer treatments such as radiation therapy or chemotherapy. If they do receive any other therapies in-between the first and second infusion of T cells, they will be taken off treatment and will not be able to receive the second infusion of T cells.
  To learn more about the way the CD30.CAR T cells are working and how long they last in the body, extra blood will be drawn.
  If the subject has stable disease (the lymphoma did not grow) or there is a reduction in the size of his/her lymphoma on imaging studies after the 2nd T-cell infusion and s/he has a negative result for a HAMA test, subjects can receive up to six additional doses of the T cells at 8 to 12 weeks intervals if desired.
  Because of the nature of this study, subjects will be followed for up to 15 years after treatment.

Eligibility: PROCUREMENT Inclusion Criteria:
  -  Diagnosis of relapsed/refractory HL or NHL or, if newly diagnosed, patient is unable to receive or complete standard therapy.
  -  CD30 positive tumor (result can be pending at this time)
  -  Hgb > 8.0 (may be a transfused value)
  -  Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent.
  -  Karnofsky or Lansky score of > 60%
  TREATMENT Inclusion Criteria:
  -  Diagnosis of relapsed/refractory HL or NHL or, if newly diagnosed, patient is unable to receive or complete standard therapy.
  -  CD30-positive tumor
  -  Bilirubin 1.5 times or less than the upper limit of normal.
  -  AST 3 times or less than the upper limit of normal.
  -  Estimated GFR > 50 mL/min.
  -  Pulse oximetry of > 90% on room air
  -  Karnofsky or Lansky score of > 60%.
  -  Available autologous T cells with greater than or equal to 15% expression of CD30CAR determined by flow-cytometry.
  -  Recovered from all acute non-hematologic toxic effects of all prior chemotherapy.
  -  Adequate pulmonary function with FEV1, FVC and DLCO greater than or equal to 50% of expected corrected for hemoglobin.
  -  Sexually active patients must be willing to utilize one of the more effective birth control methods during the study and for 6 months after the study is concluded. The male partner should use a condom.
  -  Informed consent explained to, understood by and signed by patient or guardian.
  PROCUREMENT Exclusion Criteria
  - Active infection with HIV or HTLV (can be pending at this time).
  TREATMENT Exclusion Criteria
  -  Currently receiving any investigational agents or received any tumor vaccines within the previous six weeks.
  -  Received anti-CD30 antibody-based therapy within the previous 4 weeks.
  -  History of hypersensitivity reactions to murine protein-containing products.
  -  Pregnant or lactating.
  -  Tumor in a location where enlargement could cause airway obstruction.
  -  Current use of systemic corticosteroids at a dose equivalent to 0.5 mg/kg/day of prednisone or higher.
  -  Active hemorrhagic cystitis
  -  Symptomatic cardiac disease

Relevance to patient case: not relevant