CASPALLO: Allodepleted T Cells Transduced With Inducible Caspase 9 Suicide Gene

• To determine the number of suicide gene-modified allodepleted donor lymphocytes that can be given to recipients of haploidentical stem cell transplants that will result in a rate of Grade III/IV GVHD of 25% or less. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
• To evaluate the biological and clinical effects of administration of AP1903, a dimerizer used to activate the suicide gene mechanism, in patients who develop Grade 3 or 4 GVHD. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

• To analyze the contribution of the gene-modified cells to immune reconstitution in these patients by measuring their survival, persistence and expansion [ Time Frame: 15 years ] [ Designated as safety issue: Yes ]
• To measure the overall and disease free survival, at 100 days and at 1 year [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

Patients are being asked to participate in this study because they will be receiving a stem cell transplant as treatment for their disease. As part of the stem cell transplant, they will be given very strong doses of chemotherapy, after which their stem cells would be killed. Stem cells are created in the bone marrow. They grow into different types of blood cells that they need, including red blood cells, white blood cells, and platelets.

We have identified a close relative of the patients whose stem cells are not a perfect match for the patient, 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 graft-versus-host disease (GVHD) and a longer delay in the recovery of the immune system. Seventy to ninety percent (70-90%) of the people who receive unchanged marrow or stem cells from this type of donor will develop severe GVHD.

GvHD is a serious and sometimes fatal side effect of stem cell transplant. GvHD occurs when the new donor cells recognize that the body tissues of the patient are different from those of the donor. When this happens, cells in the graft may attack the host organs, primarily the skin, liver and intestines causing severe rashes, diarrhea, liver disease, and even death. GvHD is caused by a type of immune cell in the graft called T cells. Because there is a high risk of GVHD with the type of transplant the patient will receive we will select the stem cells and remove the T cells from the graft that the patient will receive. This process which is called "CD34 selection" is discussed in more detail in the separate consent for the transplant.

While this stem cell selection procedure will reduce the risk of GvHD, it will also result in slower recovery of the immune system. As the immune system is responsible for fighting infections in the body, a longer recovery time after a transplant means that the patient may be at increased risk for infections which can become life threatening. In some patients the immune system can also fight leukemia cells and reduce the risk of relapse.

In the laboratory, we have seen that cells made to carry a gene called iCasp9 can be killed when they encounter a specific drug called AP1903. To get the iCasp9 into the T cells, we insert it using a virus called a retrovirus that has been made for this study. The drug (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. Other drugs that kill or damage T cells have helped GvHD in many studies. But we do not yet know if AP1903 will kill T cells in humans even though it has worked in our experimental studies on human cells in animals. Nor do we know if killing the T cells will help the GvHD. Because of this uncertainty, if the patient develops significant GvHD the patient will also receive standard therapy for this complication, in addition to the experimental drug. We hope that having this safety switch in the T cells will let us give higher doses of T cells that will make the immune system recover faster. These specially treated "suicide gene" T cells are an investigational product not approved by the Food and Drug Administration.

Because the patient 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.

Before the conditioning treatment for the transplant, we collected 30ml (6 teaspoonfuls) of blood from the patient which we made into a cell line that grows in the laboratory by mixing the blood with a virus called EBV. Some of the cells from this blood were mixed with T cells from the blood stem cell donor to stimulate cells that might cause GVHD. We then added an investigational agent called RFT5-dgA. The RFT5-dgA helped to get rid of donor T cells that might cause GVHD. To get iCasp9 into the remaining T cells, we have to insert the iCasp9 gene into these cells. This is done with a virus called a retrovirus that has been made for this study and will carry the iCasp9 gene into the T cells. The virus also has another gene called CD19 which will make the cells express the CD19 protein on their surface. We will not inject the virus directly into the patient but only into the special T cells we have made in the laboratory. After we have put the virus into the cells we will put the cells over a column to select the T cells that have CD19 on their surface so we know these cells will also have the iCasp9 gene. We will perform tests on the specially treated cells before giving them to the patient to ensure they only carry the iCasp9 gene, and not the virus itself. This should ensure that no virus can come out of the cells and infect other cells in the body.

TREATMENT PLAN:

To prepare the body for transplantation, the patient will be given high dose chemotherapy. Further discussion of the treatment plan for the stem cell transplant will be discussed with the patient separately and they will sign a separate consent form.

If the patient is doing well after the transplant and they do not have serious GvHD they will be eligible to receive the special T cells from Day 30 to 90 post transplant. The specially selected and treated T cells will be given by vein, once. The cells will be given between Day 30 and day 90 after the patient receives their stem cell transplant. We will give special medicines before the IV starts to help prevent allergic reactions that might occur. Because there is a possibility that the specially treated T cells can cause or worsen GVHD, we will not be able to give these cells if the patient already has significant GvHD.

If the patient develops GvHD after being given the specially treated T cells, we will prescribe the new drug that has been shown to kill cells carrying iCasp9. The drug's name is AP1903. It has been tested in normal healthy volunteers and has not caused any bad effects but is not approved by the FDA. Although the drug is not approved by the FDA, the FDA has allowed us to use the drug for this study. This drug will be given as a 2-hour intravenous infusion. We will take 10mls (2 teaspoonfuls) of blood on days 2,4 7 and 14 after the infusion to check if the drug has been successful in killing the specially treated cells. If you have mild GvHD and if the GvHD does not get better with AP1903, we will give the patient additional medicines that are usually used to treat GVHD. If the patient has serious GvHD we will give additional medicines that are usually used to treat GvHD as well as AP1903 immediately. In some cases though GvHD does not respond to treatments.

• Acute Lymphoblastic Leukemia
• Non-Hodgkin's Lymphoma

INCLUSION CRITERIA:

At the time of transplant:

A. Patients (up to 65 years of age) with:

1. ALL or high grade NHL that is Stage III or IV and has relapsed or is considered to be primary refractory disease.
2. Myelodysplastic syndrome.
3. AML after first relapse or with primary refractory disease.
4. CML
5. Hemophagocytic lymphohistiocytosis (HLH), familial hemophagocytic lymphohistiocytosis (FLH), viral-associated hemophagocytic syndrome (VAHS), patients with Severe chronic active Epstein Barr virus infection (SCAEBV) with predilection for T or NK cell malignancy, X-linked lymphoproliferative disease (XLP);

B. Lack of 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.

Inclusion Criteria at time of allodepleted T cell infusion:

1. Engrafted with ANC greater than 500.
2. Must have greater than or equal to 50% donor chimerism in either peripheral blood or bone marrow or relapse of their original disease.
3. Life expectancy greater than 30 days
4. Lansky/Karnofsky scores 60 or greater
5. Absence of severe renal disease (Creatinine greater than 2X normal for age)
6. Absence of severe hepatic disease (direct bilirubin greater than 2mg/dl, or SGOT greater than 200
7. O2 sat greater than 94% on room air
8. Patient/Guardian able to give informed consent.

EXCLUSION CRITERIA:

At the time of transplant:

1. Pregnant*

At the time of allodepleted T cell infusion:

1. GVHD
2. Severe intercurrent infection
3. Pregnant*

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 has received a reduced intensity conditioning regimen.

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