Activated T Lymphocytes Expressing CARs, Relapsed CD19+ Malignancies Post-Allo HSCT(CARPASCIO)
Activated T Lymphocytes Expressing CARs, Relapsed CD19+ Malignancies Post-Allo HSCT(CARPASCIO)
Patients have a type of lymph gland cancer called Non-Hodgkin Lymphoma (NHL), acute
 lymphocytic leukemia (ALL) or chronic lymphocytic leukemia (CLL) (these diseases will be
 referred to as "lymphoma" or "leukemia"). The lymphoma or leukemia has come back or has not
 gone away after treatment (including the best treatment known for these cancers). Because
 there is no standard treatment for this cancer at this time, subjects are asked to volunteer
 to be in a gene transfer research study using special immune cells.

 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. 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 cells 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. This antibody sticks to cancer cells
 because of a substance on the outside of these cells called CD19. CD19 antibodies have been
 used to treat people with lymphoma and leukemia. For this study, the CD19 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. The T
 lymphocytes will also contain CD28, which stimulates T cells and makes them last longer.

 Treatment with CD19/CD28 chimeric receptor-T cells has had activity against lymphoma and
 leukemia when the cells are made from the patients affected by these diseases. In this study,
 investigators are going to see if this treatment works even better when they make these cells
 from a healthy stem cell donor. If investigators are not able to collect blood from the stem
 cell donor, they will collect blood from the subject to make the CD19/CD28 chimeric
 receptor-T cells.

 These CD19/CD28 chimeric receptor T cells are investigational products not approved by the
 FDA.

 The purpose of this study is to find the biggest dose of chimeric T Cells that is safe, to
 see how long T cells with this chimeric receptor last, to learn what the side effects are,
 and to see whether this therapy might help people with lymphoma or leukemia after a stem cell
 transplantation from a donor.
The subject or his/her donor will give blood to make CD19/CD28 chimeric receptor-T cells in
 the laboratory. These cells will be grown and frozen. To make the T cells, the
 donor/subject's blood will be stimulated with growth factors to make the T cells grow. To get
 the CD19 antibody with CD28 to attach to the surface of the T cell, an antibody gene will be
 inserted 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
 investigators find the T cells in the blood using a special laboratory test. Subjects will be
 followed for a total of 15 years to see if there are any long term side effects of gene
 transfer.

 When a subject enrolls on this study, s/he will be assigned a dose of CD19/CD28 chimeric
 receptor-T cells and should not receive other cancer treatment until 6 weeks after cell
 infusion.

 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 subject's level of circulating T cells is relatively
 high, s/hemay receive treatment with cyclophosphamide (Cytoxan) and fludarabine (chemotherapy
 drugs) before the T cells. If the subject is already receiving chemotherapy, this may not be
 needed.

 The subject will be given an injection of cells into the vein through an IV at the assigned
 dose. The injection will take up to 10 minutes. The research staff will follow the subject in
 the clinic after the injection for up to 4 hours. If after a 4-6 week evaluation period after
 the infusion, the subject seems to be experiencing a benefit (confirmed by radiological
 studies, physical exam and/or symptoms), s/he may be able to receive up to 5 additional doses
 of the T cells. These additional infusions would be at least 4-6 weeks apart and at the same
 dose level received the first time or a lower dose.

 There will be medical tests during and after treatment. To learn more about the way the CD19
 chimeric receptor-T cells are working and how long they last in the body, extra blood will be
 drawn.
Inclusion Criteria:

 PROCUREMENT

 -  Group A: CD19+ B-ALL undergoing allogeneic HSCT or Group B: CD19+ B cell CLL or NHL
 undergoing allogeneic HSCT

 -  Life expectancy of ≥12 weeks.

 -  Patient has an appropriate donor identified for hematopoietic stem cell
 transplantation

 TREATMENT

 -  Any patient regardless of sex or age with CD19+ B-ALL undergoing allogeneic HSCT
 (Group A) OR any patient regardless of sex or age with CD19+ B-CLL or NHL undergoing
 allogeneic HSCT (Group B)

 -  Residual disease at the time of transplant (bulky or minimal) or post transplant
 relapse as evidenced by PCR positivity, specific cytogenetic abnormalities, an
 abnormal population on flow cytometry or increased blasts on bone marrow biopsy or in
 the peripheral blood. MRD will be defined as detection in blood or marrow of any of
 the following:

 -  Any leukemia specific marker (such as t(9:22) or t(4:11)) documented in the
 patient's leukemia cells pre transplant on a post transplant evaluation.

 -  An immune globulin rearrangement known to be a disease marker for this patient
 post transplant.

 -  A leukemia specific phenotype post transplant at a level of ≥ 0.01%

 -  Mixed donor chimerism (any level)

 -  Life expectancy ≥ 6 weeks

 -  Karnofsky/Lansky score ≥ 50%.

 -  Bilirubin ≤ 2 times the upper limit of normal.

 -  AST ≤ 3 times the upper limit of normal.

 -  Estimated GFR > 50 mL/min

 -  Hgb ≥ 7.0 (can be a transfused value)

 -  Pulse oximetry of > 90% on room air

 -  Sexually active patients must be willing to utilize one of the more effective birth
 control methods during the study and for 6 months after ATL infusion. The male partner
 should use a condom.

 -  Available allogeneic activated peripheral blood T cell products with >=15% expression
 of CD19.CAR-CD28ζ determined by flow cytometry (cell dose is based on total cell
 numbers and not individual antileukemic cell numbers).

 -  No other investigational antitumor therapy for one month prior to entry in this study.

 -  Patients or legal guardians must sign an informed consent.

 Exclusion Criteria:

 -  Severe intercurrent infection.

 -  Evidence of GVHD > grade II.

 -  Pregnant or lactating.

 -  History of hypersensitivity reactions to murine protein-containing products.

 -  Currently taking corticosteroids (>0.5 mg/kg/day prednisone or equivalent) for therapy
 of GVHD.