Study of the T-cells or EBV Specific CTLs for Advanced B-Cell Non Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia (ATECRAB)

• To measure the differential survival and function of CD19CAR transduced PBTLs and EBV-CTLs in vivo, in particular to determine if CD19CAR transduced EBV-CTLs survive longer than CD19CAR-CD28 transduced PBTLs. [ Time Frame: 15 years ] [ Designated as safety issue: No ]
• To measure the anti-tumor effects of CD19CAR transduced T- lymphocytes in patients with low and intermediate-grade NHL or B-CLL. [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]

• To measure the differential survival and function of CD19CAR transduced PBTLs and EBV-CTLs in vivo, in particular to determine if CD19CAR transduced EBV-CTLs survive longer than CD19CAR-CD28 transduced PBTLs. [ Time Frame: 15 years ] [ Designated as safety issue: Yes ]
• To measure the anti-tumor effects of CD19CAR transduced T- lymphocytes in patients with low and intermediate-grade NHL or B-CLL. [ Time Frame: 15 years ] [ Designated as safety issue: Yes ]

Patients on this study have a type of lymph gland cancer called non-Hodgkin Lymphoma or chronic Lymphocytic Leukemia. Their lymphoma or CLL has come back or has not gone away after treatment. Because there is no standard treatment for the cancer at this time or because the currently used treatments do not work fully in all cases, patients are being asked to volunteer to take part in a gene transfer research study using special immune cells.

The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise, but have not been strong enough to cure most patients.

The antibody used in this study is called anti-CD19. This antibody sticks to lymphoma cells because of a substance on the outside of these cells called CD19. CD19 antibodies have been used to treat people with lymphoma and CLL. For this study, the anti-CD19 antibody has been changed so that instead of floating free in the blood it is now attached to T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These chimeric receptor-T cells seem to be able to kill tumors like the one the patient has, but they don't last very long and so their chances of fighting the cancer are limited. Therefore, developing ways to prolong the life of these T cells should help them fight cancer.

We found that T cells work better if we also attach a protein called CD28 to the T cells. This protein makes the T cells more active and survive longer. By joining the anti-CD19 antibody to the T cells and adding the CD28, we expect to be able to make cells that will last for a longer time in the body and recognize and kill the lymphoma cells.

We also found that T cells that are also trained to recognize the virus that causes infectious mononucleosis (called Epstein Barr Virus or EBV) can stay in the blood stream for many years. By joining the anti-CD19 antibody to the cytotoxic T lymphocytes (CTLs) that recognize EBV, we believe that we will also be able to make a cell that can last a long time in the body and recognize and kill lymphoma cells.

In this study we are going to see which of these methods of prolonging T cell activity is better. Half of the cells will have the CD19 chimeric receptor with CD28 put on them. The other half will be selected and expanded based on their ability to recognize EBV and will have the CD19 chimeric receptor without CD28 put on them. Both cell populations will be reinfused in the body and, by analyzing your blood periodically, we will be able to see if there is a difference in how long they last. These CD19-CD28 chimeric receptor T cells and CD19 chimeric-EBV specific T cells are investigational products not approved by the Food and Drug Administration.

The patient or their donor will give us blood to make CD19-CD28 chimeric receptor T cells and CD19 chimeric-EBV specific T cells in the laboratory. These cells are grown and frozen for the patient. Because the patient will have received cells with a new gene in them they will be followed for a total of 15 years to see if there are any long term side effects of gene transfer.

The patient will be assigned a dose of CD19-CD28 chimeric receptor-T cells and CD19 chimeric receptor-EBV specific T cells. Several studies suggest that the infused T cells need room to be able to proliferate and accomplish their functions and that this may not happen if there are too many other T cells in circulation. Because of that, if the patient's level of circulating T cells is relatively high, they will receive one treatment of cyclophosphamide. This drug will decrease the numbers of the patient's own T cells before we infuse the CD19 chimeric receptor T cells. Although we do not expect any effect on your tumor with the dose that you will receive, this drug is part of many regimens that are used to treat lymphoma or CLL. If you are already receiving chemotherapy, thi smay not be needed.

The patient will be given an injection of cells into the vein through an IV line at the assigned dose. The patient will be followed in the clinic after the injection for up to 3 hours. If after a 4-6 week evaluation period after the infusion, the patient seems to be experiencing a benefit (confirmed by radiological studies, physical exam and/or symptoms), they may be able to receive up to three additional doses of the T cells. These additional infusions would be at least 4-6 weeks apart and at the same dose level the patietn received the first time.

Before being treated, the patient will receive a series of standard medical tests: Physical exam, Blood tests to measure blood cells, kidney and liver function Measurements of the tumor by scans and/or bone marrow studies

Medical tests during and after treatment:

The patient will receive standard medical tests when they are getting the infusions and after: Physicalexams, Blood tests to measure blood cells, kidney and liver function, Measurements of the tumor by scans and/or bone marrow studies 6 weeks after the infusion

To learn more about the way the CD19-CD28 chimeric receptor T cells and CD19 chimeric receptor-EBV specific T cells are working and how long they last in the body, extra blood will be drawn at the following timepoints: On the day of the infusion blood will be taken before the cells are given and several hours afterwards. Other blood will be drawn one week after the infusion, 2 weeks, 4 weeks and 6 weeks after the infusion, every 3 months for 1 year, every 6 months for 4 years, then yearly for a total of 15 years.

• Non-Hodgkin Lymphoma
• Chronic Lymphocytic Leukemia

INCLUSION CRITERIA:

FOR TREATMENT:

• Recurrent low or intermediate grade B-cell lymphoma or B-CLL, or newly diagnosed patients unable to receive or complete standard therapy OR diagnosis of relapsed/refractory intermediate B cell lymphoma with a treatment plan that will include high dose therapy and autologous stem cell transplantation.
• CD19-positive tumor
• EBV seropositivity (in patient and donor, as applicable)
• Recovered from the acute toxic effects of all prior chemotherapy at least a week before entering this study.
• Not be currently receiving any investigational agents or have not received any tumor vaccines within the previous six weeks.
• No treatment with rituximab within the previous 8 weeks.
• ANC > 500, Hgb > 8.0*
• Bilirubin less than 3 times the upper limit of normal*
• AST less than 5 times the upper limit of normal*
• Serum creatinine less than 3 times upper limit of normal*
• Pulse oximetry of > 90% on room air*
• Adequate pulmonary function with FEV1, FVC and DLCO >35%* of expected corrected for hemoglobin
• Karnofsky or Lansky score of > 60%.
• Available autologous or syngeneic transduced EBV-specific cytotoxic T lymphocytes and peripheral blood T-cells with 15% or greater expression of CD19CAR determined by flow-cytometry.
• Patients or legal guardians must understand and sign an informed consent indicating that they are aware this is a research study and have been told of its possible benefits and toxic side effects. Patients or their guardians will be given a copy of the consent form.
• Sexually active patients must be willing to utilize one of the more effective birth control methods during the study and for 3 months after the study is concluded. The male partner should use a condom.

EXCLUSION CRITERIA:

• History of hypersensitivity reactions to murine protein-containing products.
• Pregnant or lactating.
• Tumor in a location where enlargement could cause airway obstruction.
• Active infection with HIV, HBV, HCV or CMV.

• Center for Cell and Gene Therapy, Baylor College of Medicine
• Texas Children's Hospital
• The Methodist Hospital System