Administration of Donor T Cells With the Caspase-9 Suicide Gene

Patients will be receiving a stem cell transplant as treatment for their disease. As part of the stem cell transplant, patients will be given very strong doses of chemotherapy, which will kill all their existing stem cells. A close relative of the patient will be identified, whose stem cells are not a perfect match for the patient's, but can be used. This type of transplant is called "allogeneic", meaning that the cells are from a donor. With this type of donor who is not a perfect match, there is typically an increased risk of developing GvHD, and a longer delay in the recovery of the immune system. GvHD is a serious and sometimes fatal side-effect of stem cell transplant. GvHD occurs when the new donor cells (graft) recognize that the body tissues of the patient (host) are different from those of the donor. In this study, investigators are trying to see whether they can make special T cells in the laboratory that can be given to the patient to help their immune system recover faster. As a safety measure, we want to "program" the T cells so that if, after they have been given to the patient, they start to cause GvHD, we can destroy them ("suicide gene"). Investigators will obtain T cells from a donor, culture them in the laboratory, and then introduce the "suicide gene" which makes the cells sensitive to a specific drug called AP1903. If the specially modified T cells begin to cause GvHD, the investigators can kill the cells by administering AP1903 to the patient. We have had encouraging results in a previous study regarding the effective elimination of T cells causing GvHD, while sparing a sufficient number of T cells to fight infection and potentially cancer. More specifically, T cells made to carry a gene called iCasp9 can be killed when they encounter the drug AP1903. To get the iCasp9 gene into T cells, we insert it using a virus called a retrovirus that has been made for this study. The AP1903 that will be used to "activate" the iCasp9 is an experimental drug that has been tested in a study in normal donors with no bad side-effects. We hope we can use this drug to kill the T cells. The major purpose of this study is to find a safe and effective dose of "iCasp9" T cells that can be given to patients who receive an allogeneic stem cell transplant. Another important purpose of this study is to find out whether these special T cells can help the patient's immune system recover faster after the transplant than they would have otherwise.

Sex

All

Inclusion Criteria:

Inclusion Criteria at Time of Procurement:

1. Lack of a suitable conventional donor (i.e. 5/6 or 6/6 related, or 5/6 or 6/6 unrelated donor), or presence of a rapidly progressive disease not permitting time to identify an unrelated donor.
2. High risk disease in one of the following:

   * Myelodysplastic syndrome (MDS) in one of the following categories: RCMD with an IPSS-R of intermediate, poor, or very poor, RAEB-1, or RAEB-2
   * Acute myeloid leukemia (AML) after first relapse or primary refractory disease
   * Chronic myelogenous leukemia (CML) in Chronic Phase 2 or greater, Accelerated Phase or Blast Crisis
   * Acute lymphoblastic leukemia (ALL) after first relapse or primary refractory disease, or High-Grade Non Hodgkin lymphoma (NHL) Stage III or IV after first relapse or primary refractory disease
   * Hemophagocytic lymphohistiocytosis (HLH)
   * Familial hemophagocytic lymphohistiocytosis (FLH)
   * Viral-associated hemophagocytic syndrome (VAHS)
   * T or NK cell lymphoproliferative syndrome
   * X-linked lymphoproliferative disease (XLP)

Inclusion Criteria at Time of T Cell Infusion:

1. Engrafted with an absolute neutrophil count (ANC) \> 500 cells/µL
2. Greater than or equal to 50% donor chimerism in either peripheral blood or bone marrow, or relapse of their original disease
3. Life expectancy \> 30 days
4. Lansky/Karnofsky score greater than or equal to 60
5. Absence of severe renal disease (creatinine \> 2X upper limit of normal for age)
6. Absence of severe hepatic disease (direct bilirubin \> 3X upper limit of normal or SGOT \> 3X upper limit of normal)
7. Oxygen saturation \> 94% on room air
8. Patient/Guardian able to give informed consent
9. AP1903 available in sufficient quantities to allow for treatment of the patient

Exclusion Criteria:

Exclusion Criteria at Time of T Cell Infusion:

1. GvHD
2. Severe intercurrent infection
3. Pregnancy\*
4. Other investigational drugs in the prior 30 days

   * Pregnancy test only required for at-risk individuals, defined as female patients of childbearing potential who have received a reduced-intensity conditioning regimen.

• DERIVEDZhou X, Dotti G, Krance RA, Martinez CA, Naik S, Kamble RT, Durett AG, Dakhova O, Savoldo B, Di Stasi A, Spencer DM, Lin YF, Liu H, Grilley BJ, Gee AP, Rooney CM, Heslop HE, Brenner MK. Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation. Blood. 2015 Jun 25;125(26):4103-13. doi: 10.1182/blood-2015-02-628354. Epub 2015 May 14. PMID 25977584