CD19 Chimeric Receptor Expressing T Lymphocytes In B-Cell Non Hodgkin's Lymphoma And Chronic Lymphocytic Leukemia (CRETI-NH)

• Measure the survival and function of CD19CAR T cells in vivo [ Time Frame: 15 years ] [ Designated as safety issue: No ]
• To compare two different T-cell products in the same patient in which the CD19CAR will differ only by the inclusion of the CD28 co-stimulatory endodomain. [ Time Frame: 15 years ] [ Designated as safety issue: No ]
• To measure the anti-tumor effects of chimeric CD19 receptor transduced autologous T- lymphocytes in patients with Low-grade non-Hodgkin's Lymphoma (NHL) or Chronic Lymphocytic leukemia (B-CLL). [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]

• Measure the survival and function of CD19CAR T cells in vivo [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
• To compare two different T-cell products in the same patient in which the CD19CAR will differ only by the inclusion of the CD28 co-stimulatory endodomain. [ Time Frame: 5 years ] [ Designated as safety issue: No ]
• To measure the anti-tumor effects of chimeric CD19 receptor transduced autologous T- lymphocytes in patients with Low-grade non-Hodgkin's Lymphoma (NHL) or Chronic Lymphocytic leukemia (B-CLL). [ Time Frame: 5 years ] [ Designated as safety issue: No ]

Patients on this study have a type of lymph gland cancer called non-Hodgkin Lymphoma or chronic Lymphocytic Leukemia (these 2 diseases will be referred to as "Lymphoma" or "CLL"). Their lymphoma or CLL has come back or has not gone away after treatment (including the best treatment we know for these cancers). Because there is no standard treatment for the cancer at this time, patients are being asked to volunteer to be in a gene transfer research study using special immune cells. Patients may have already thought a lot about being in this study. They may even have already made a decision about whether to be in the study. Even if this is true for the patient, it is important that we give the patients this information and talk about it before we start in the study.

The body has different ways of fighting infection and disease. No one way seems perfect for fighting cancers. This research study combines two different ways of fighting disease, antibodies and T cells, hoping that they will work together. Antibodies are types of proteins that protect the body from bacterial and other diseases. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells including 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.

T lymphocytes can kill tumor cells but there normally are not enough of them to kill all the tumor cells. Some researchers have taken T cells from a person's blood, grown more of them in the laboratory and then given them back to the person.

The antibody used in this study is called anti-CD19. It first came from mice that have developed immunity to human lymphoma. 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 anti-CD19 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.

In the laboratory, we have also found that T cells work better if we also put a protein that stimulates T cells called CD28. We hope that adding the CD28 might also make the cells last for a longer time in the body.

In this study we are going to see if this is true by putting the CD19 chimeric receptor alone into half the cells and the CD19 chimeric receptor with CD28 into the other half. We will then be able to see if there is a difference in how long they last. These CD19 chimeric receptor T cells and CD19 chimeric receptor with C28 T cells are investigational products not approved by the Food and Drug Administration.

Patients will give us blood to make CD19 chimeric receptor-T cells and CD19 CD28 chimeric receptor-T cells in the laboratory. These cells will be grown and frozen for the patient. To make the T cells we take the blood and stimulate it with growth factors to make the T cells grow. To get the CD19 antibody (with or without CD28) to attach to the surface of the T cell, we insert the antibody gene into the T cell. This is done with a virus called a retrovirus that has been made for this study and will carry the antibody gene into the T cell. This virus also helps us find the T cells in the blood after we inject them; in order to tell them apart we have made two viruses that are slightly different because one has CD28. These two viruses can be told apart by a special laboratory test. Because the patients will receive 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. If the patient cannot visit the clinic, they may be contacted by the research coordinator or physician.

When the patients enroll on this study, they will be assigned a dose of CD19 chimeric receptor-T cells and CD19 CD28 chimeric receptor-T cells. We would prefer that patients not receive other chemotherapy until 6 weeks after their cell infusion but they can do so if their doctor thinks it is medically necessary.

Our studies so far have shown that the infused T cells may need to receive an extra boost in order to expand efficiently in your body. Therefore, 2 weeks after T cell infusion, the patient will receive one injection of a drug called ipilimumab, which we believe will help your T cells grow. This drug is approved by the FDA to treat certain cancers, such as melanoma, but the dose of drug that we will use for this study will be lower than those used in those other treatments to avoid side effects.

Patients will be given an injection of cells into the vein through an IV at the assigned dose. Before they receive the injection, they may be given a dose of Benadryl and Tylenol. The injection will take about 20 minutes. We will follow the patients in the clinic after the injection for up to 3 hours. If after a 4-6 week evaluation period after the infusion, the patient seem 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 if they wish. These additional infusions would be at least 4-6 weeks apart and at the same dose level they received the first time or a lower dose. The treatment will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital or The Methodist Hospital.

Medical tests before treatment--

Before being treated, they will receive a series of standard medical tests:

• Physical exam and History
• 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:

• Physical exams and History
• Blood tests to measure blood cells, kidney, liver, and thyroid 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 chimeric receptor-T cells and CD19 CD28 chimeric receptor-T cells are working and how long they last in the body, extra blood will be drawn. The total amount on any day is about 10 teaspoons (50 mL). On the day they receive the cells, 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, at 3 months, at 6 months, at 9 months, at 1 year, every 6 months for 4 years, then yearly for a total of 15 years. The total blood drawn during the patients participation in this study will not exceed 280 teaspoons.

If the patients have a biopsy of their tumor or bone marrow studies in the future after completing this study, we may ask to have a piece of tumor or bone marrow to look for CD19 chimeric receptor-T cells and CD19 CD28 chimeric receptor-T cells.

• B Cell Lymphoma
• Chronic Lymphocytic Leukemia

• Genetic: CD19CAR-zeta and CD19CAR-28-zeta T cells

  Intravenous injection over 1 to 10 minutes

  Dose Level 1:

  CD19CAR - 2x10^7 cells/m^2

  CD19CAR-28 - 2x10^7 cells/m^2

  Dose Level 2:

  CD19CAR - 1x10^8 cells/m^2

  CD19CAR-28 - 1 x10^8 cells/m^2

  Dose Level 3:

  CD19CAR - 2x10^8 cells/m^2

  CD19CAR-28 - 2x10^8 cells/m^2

  Other Names:

  • CD19CAR
  • CD19CAR-28
• Drug: Ipilimumab
  Patients will receive ipilimumab once during the week 2 visit after the T cell infusion.
  Other Name: Yervoy

INCLUSION CRITERIA:

Patients must meet the following eligibility criteria to be included:

1. Recurrent low grade or intermediate grade B cell lymphoma or 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
2. Life expectancy of at least 12 weeks
3. Recovered from the toxic effects of all prior chemotherapy before entering this study
4. ANC greater than 500, HgB greater than 8.0
5. Bilirubin less than 3 times the upper limit of normal
6. AST less than 5 times the upper limit of normal
7. Serum creatinine less than 3 times upper limit of normal
8. Pulse oximetry of greater than 90% on room air
9. Karnofsky/Lansky score of greater than 60%
10. Available autologous transduced peripheral blood T-cells with greater than/=15% expression of CD19CAR determined by flow-cytometry
11. Patients or legal guardians must 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
12. 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:

1. History of hypersensitivity reactions to murine protein-containing products
2. Pregnant or lactating
3. Tumor in a location where enlargement could cause airway obstruction
4. Currently receiving any investigational agents or have not received any tumor vaccines within the previous six weeks

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