Infusion of Genetically Modified T Cell for Post Transplant Patients With Relapsed Disease

This is a phase I study of to determine the safety of the administration of lymphocytes,
collected from the bone marrow donor. Donor lymphocytes are often administered in the case
of a relapsed cancer after allogeneic bone marrow transplantation, in the hope to reduce the
amount or size of the relapsed cancer. In this study, we will look for a decrease of the
size of the relapsed cancer.

By inserting genetic material (DNA) into the cells (lymphocytes) collected from the donor,
these cells will be genetically modified and made very sensitive to the killing effects of a
drug called ganciclovir, routinely used in the clinic after bone marrow transplantation to
treat virus infections in transplant patients.

This research study is to determine, if administration of the drug ganciclovir to the
recipient, after intravenous infusion of the genetically modified cells (lymphocytes) into
the recipient, will reduce or even eliminate a life threatening complication of allogeneic
transplantation, called graft versus host disease (GvHD). The drug ganciclovir will kill the
infused genetically modified donor cells (lymphocytes) so they cannot cause GvHD.

In summary, the overall purpose of this research study is to determine, if administration of
a seven day course of the drug ganciclovir to the donor lymphocyte recipient will either
decrease the severity of GvHD, or will decrease the number of cases with life-threatening
GvHD after donor lymphocyte infusions.

This study will also determine if insertion of a small piece of DNA (a small piece of
genetic material), makes these donor lymphocytes opened up and sensitive to the killing
effects of the drug ganciclovir, but at the same time does not harm the lymphocytes' ability
to reduce the amount or size of the cancer in the recipient. The DNA to be inserted into the
donor lymphocytes is transported into these cells by a type of virus called "retrovirus
vector". This retrovirus vector is made so the virus cannot divide (cannot make more of
itself), and cannot make cells or the recipient sick. Retroviruses do, however, allow for
the gene (DNA) they are carrying, to be permanently inserted into the genetic material of
the donor lymphocytes. Therefore, this inserted DNA will persist in the donor lymphocytes
for the life of the lymphocytes.

Finally, this study will also determine if the administration of genetically manipulated
donor lymphocytes is well tolerated.

Sub Study

The goal of this subproject is to see if an imaging procedure called 18FHBG-PET/CT can help
us see if the lymphocytes you received have gone to the sites in the body where the
anti-cancer effects are taking place.

Inclusion Criteria:

Patient Criteria

Patients must meet the following criteria within 30 days prior to study entry (Day 0)
unless otherwise noted:

- Patients must be prior recipients of allogeneic BMT (matched 6/6 or 5/6 according to
the National Marrow Donor Program) for any hematologic malignancy. Eligible patients
would include those with leukemia, non Hodgkins Lymphoma, Hodgkins Disease,
myelodysplastic syndrome and multiple myeloma.

- Patients must have laboratory, histologic, or cytogenetic evidence of disease relapse
after allogeneic BMT.

- Patients may not have received prior therapy with transduced or non-transduced donor
lymphocytes.

- Patients ≥ 18 years of age.

- The minimum number of transduced and purified lymphocytes from the same donor of
donated cells for allogeneic transplant is is 1x105 per kg for all patients.

- Expected survival of patient is at least 4 weeks.

- Required baseline organ function within 14 days prior to study entry:

- Renal function with creatinine less than 5 mg/dl.

- Liver function with SGOT, SGPT and alkaline phosphatase ≤ 4 times the upper limit of
institutional normal.

- Bilirubin ≤ 5.0 mg/dl.

- Patient must have signed the informed consent prior to entry and express willingness
to meet all the expected requirements of the protocol for the duration of the study.

- ECOG Performance Status ≤ 2

- All patients must agree to a repeat bone marrow, liver, gastro-intestinal or skin
biopsies dependent on clinical course.

- Women of child bearing potential must have a negative pregnancy test (ß-HCG ) within
7 days of study entry.

- In addition patients # 3 to 8:

- Must have consented to participation in HRPO 09-0744, "Infusion of Genetically
Modified T cells: A Pilot I Study of Tracking and Toxicity

- Must be willing to undergo 18FHBG-PET/CT-imaging

- Must be able to tolerate 45-60 minutes of imaging at each imaging timepoint.

- Women of child bearing potential must have an additional negative high sensitivity
pregnancy test (20mlU ß-HCG /ml urine as administered in the Center for Clinical
Imaging Research, Mallinckrodt Institute of Radiology, Washingon University) prior to
each imaging session (i.e. at days 10-16 and days 27-33).

Donor Inclusion Criteria

- Must be the original donor for the allogeneic bone marrow transplant patient.

- No underlying conditions which would contra-indicate apheresis.

- Must have signed the informed consent and express willingness to meet all the
expected requirements stated in the protocol for the duration of the study.

- Must be eligible according to Washington University "Guidelines for Eligibility of
Normal Donors"

- Donors ≥ 18 years of age.

- Female donors of childbearing potential must have a confirmed negative pregnancy
test.

Patient Exclusion Criteria

- Patients receiving immunosuppression (cyclosporin, FK506, prednisone, cellcept,
methylprednisolone) for GvHD or other reasons at the time of lymphocyte infusion.

- Patients must not have evidence of active CMV or other active viral infection
requiring antiviral therapy. A culture or PCR of blood for CMV must be negative for
enrollment.

- Pregnant or lactating females.Note that a second and third high sensitivity pregnancy
test (20mlU ß-HCG /ml urine as administered in the Center for Clinical Imaging
Research, Mallinckrodt Institute of Radiology, Washingon University) are required
prior to each imaging session (i.e. at days 10-16 and days 27-33 for patients #3 to
8). See section 8.0 of appendix 43.

- Uncontrolled infection: Any uncontrolled viral, bacterial, or fungal infection.

- HIV infection.

- Acute medical problems such as ischemic heart or lung disease.

- Patients with any underlying conditions which would contra-indicate therapy with
study treatment (or allergies to reagents used in this study).

- Patients who have received atgam, campath [alemtuzumab] or daclizumab within 4 weeks
of DLI.

- Patients receiving investigational drugs or treatments within 30 days of enrollment.

- Patients with tetracycline, penicillin, or streptomycin sensitivity.

- Patients with signs of acute GVHD as defined by the International Bone Marrow
Transplant Registry (IBMTR) Severity Index for Acute Graft versus Host Disease
(Rowlings, et al., Brit. J. Haematol. 97:855-64 [1997]). In addition patients may be
excluded at the discretion of the treating physician.

- In addition for patients # 3 to 8 who will be imaged (appendix 43), exclude:

- Patients who are claustrophobic.

- Patients who are unable to tolerate 30-45 minutes of imaging.

Donor Exclusion Criteria:

-Pregnant female donors

Concomitant Medication and Treatment:

-The principal investigator or a designated co-investigator at the respective institution
must approve use of chemotherapeutic, antiviral or immunosuppressive medications.

Medications and Treatments Not Allowed:

-No other forms of chemotherapy will be administered after cell infusion during the
treatment protocol.

Sub-Study

Inclusion Criteria

Patients must meet the following criteria:

- Patients must have consented to participation in HRPO 09-0744 "Infusion of
Genetically Modified T cells: A Phase I Study of Tracking and Toxicity".

- Patients must be willing to undergo 18FHBG PET/CT imaging.

- Patient must be able to tolerate 45-60 minutes of imaging at each imaging time point

- Patient must be 18 years of age or greater

Exclusion Criteria

- Patients who are claustrophobic

- Female patients who are pregnant or nursing.

- Patients who are unable to tolerate 30-45 minutes of imaging.