• 2.1 To determine the safety of autologous/syngeneic or allogeneic LMP-2 specific cytotoxic T-lymphocytes (CTL) in combination with CD45 monoclonal antibody (Mab) in patients with EBV positive Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL). [ Time Frame: 15 years ] [ Designated as safety issue: Yes ]
• Obtain information on expansion, persistence and anti-tumor effects of (CTL) given after lymphodepletion with CD45 monoclonal antibody (Mab) in patients with EBV positive Hodgkin's disease or non-Hodgkin's lymphoma. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]

1. To determine the safety of autologous/syngeneic or allogeneic LMP-2 specific cytotoxic T-lymphocytes (CTL) in combination with CD45 monoclonal antibody (Mab) in patients with EBV positive Hodgkins disease (HD) or non Hodgkins lymphoma (NHL).
2. To obtain information on the expansion, persistence and anti-tumor effects of of autologous/syngeneic or allogeneic LMP-2 specific cytotoxic T-lymphocytes (CTL) given after lymphodepletion with CD45 monoclonal antibody (Mab) in patients with EBV positive Hodgkins disease or non Hodgkins lymphoma.

Although we have seen some clinical benefit in our initial Hodgkin's study the CTL have not expanded as well in these patients as in patients post T cell depleted BMT, where EBV-specific CTL expanded by up at least four logs after infusion and persisted for up to 86 months. We propose that failure to expand effectively in Hodgkin's patients in part reflects a T helper 2 environment due to the T cell infiltrate at sites of disease. In this inhibitory environment, ex vivo-expanded CTL may be required to circumvent in vivo inhibition and may fail to expand or be diverted along the T helper 2 pathway despite an initial tumor-specific response. In addition to these intratumoral Th2 inhibitory cells, we propose that homeostatic mechanisms act on adoptively transferred tumor specific CTLs to prevent their expansion and long-term function in vivo in patients with a normal T cell level.

We hypothesize that the expansion, function and anti-tumor activity of infused CTL may be increased dramatically by depleting the lymphoid compartment of all T cells including negative regulatory T cells and Th2 cells by pre-treating patients. The lytic CD45 monoclonal antibody can accomplish this, and its short half-life will allow rapid infusion of therapeutic cells.

We will first test a biopsy of the patient's tumor that has already been done to see if tumor cells are EBV positive. If the patient is eligible, we will then take 60-70 ml (12-14 teaspoonfuls) of blood. We will use this blood to grow T cells. We will first grow a special type of cell called dendritic cells which will stimulate the T cells and we will put a specially produced human virus (adenovirus) that carries the LMP-2a gene into the dendritic cells. These dendritic cells will then be treated with radiation so they cannot grow. They will then be used to stimulate T cells. This stimulation will train the T cells to kill cells with LMP-2a on their surface. We will then grow these LMP-2a specific CTLs by more stimulation with EBV infected cells (which we will make from the patients blood by infecting them with EBV in the laboratory). We will also put the adenovirus that carries the LMP2 gene into these EBV infected cells so that we increase the amount of LMP2 which these cells have. Again, these EBV infected cells will be treated with radiation so they cannot grow. Once we have made sufficient numbers of T cells we will test them to make sure they kill cells with LMP2a on their surface. If the patient's counts are low we may need to obtain additional blood samples to make these cells. We will also take extra blood to freeze in case the patient's immune system is slow to recover after the antibody infusions.

1. CD 45 Infusions A fixed dose of CD45 MAb will be used determined from our previous and ongoing studies in stem cell transplant recipients will be used36, 400ug/kg over 4 hrs daily x 4 given as two daily intravenous infusions that will be completed 48-72 hours prior to CTL infusion. Patients will be premedicated prior to CD45 infusions and monitored as per the SOP for CD45 infusion.

   Day 1 YTH 24/54 400ug/kg over 6 to 8 hr

2. YTH 24/54 400ug/kg over 6 to 8 hr
3. YTH 24/54 400ug/kg over 6 to 8 hr
4. YTH 24/54 400ug/kg over 6 to 8 hr
5. Rest 6-8 CTL Infusion (provided CD45 Mab level <100 ug/ml)

Dose Levels of CTLs

The following dose levels will be evaluated: Each patient will receive 1 injection, according to the following dosing schedules:

2x 107 cells/m2 5 x 107 cells/m2

1 x 108 cells/m2

Patients will be pre-medicated with Benadryl 1mg/kg IV (max 50) and Tylenol 10mg/kg po (max 650).

Cell Administration EBV specific T cells will be given by intravenous injection over 1-10 minutes through either a peripheral or a central line.

• Biological: CD45 antibodies
• Biological: EBV specific T cells

• Experimental: Patients receiving CTLs as therapy for relapsed Lymphoma or who are at high risk for relapse or patients receiving CTLs as adjunctive therapy following autologous or syngeneic transplant
• Experimental: Patients receiving CTLs following allogeneic stem cell transplant

Inclusion Criteria:

• Any patient, regardless of age or sex, with EBV-positive Hodgkin's or non-Hodgkin lymphoma, regardless of the histological subtype or EBV-associated T/NK cell Lymphoproliferative disease. This includes patients in second or subsequent relapse including post autologous or syngeneic stem cell transplant (or with active disease or in first relapse if immunosuppressive chemotherapy contraindicated or if the patient has relapsed multiple times and is currently in remission but has a high risk of relapse). (group A) OR Patients who have relapsed after allogeneic stem cell transplant for Hodgkin's Lymphoma or non-Hodgkin's Lymphoma (Group B)
• Life expectancy of more than 6 weeks.
• No severe intercurrent infection
• Patient, parent/guardian able to give informed consent
• HIV negative
• Bilirubin less than or equal to 3x normal
• AST less than or equal to 5x normal,
• Hgb higher than 8.0 g/L
• Creatinine less than or equal to 2x normal for age
• Patients should have been off other investigational therapy including T cells therapies for one month prior to entry in this study.
• Karnofsky score of over or equal to 50.
• Female patients with reproductive capacity must have a negative pregnancy test.

Exclusion Criteria:

• Patient, parent/guardian unable or unwilling to give informed consent
• HIV positive
• Pregnant women
• Patients with a Karnofsky score of < 50
• Patients with a severe intercurrent infection
• Patients with a life expectancy of <6 weeks
• Patients with a bilirubin of more than 3x normal. AST of more than 5x normal
• Patients with a creatinine of more than 2x normal for age
• Due to unknown effects of this therapy on a fetus, pregnant women are excluded from this research. The male partner should use a condom.

• The Methodist Hospital System
• Texas Children's Hospital
• Center for Cell and Gene Therapy