Patients have a type of lymph gland disease called Hodgkin or non-Hodgkin lymphoma which has come back, or may come back, or has not gone away after treatment, including the standard treatment known for these diseases. This a research study using special immune system cells called tumor associated antigen (TAA)-specific cytotoxic T lymphocytes, a new experimental therapy.

This sort of therapy has been used previously to treat Hodgkin or non-Hodgkin lymphomas that show proof of infection with Epstein-Barr virus (EBV), the virus that causes infectious mononucleosis ("mono" or the "kissing disease"). EBV is found in cancer cells of up to half of all patients with Hodgkin's and non-Hodgkin lymphoma. This suggests that it may play a role in causing lymphoma. The cancer cells infected by EBV are able to hide from the body's immune system and escape being killed. Investigators tested whether special white blood cells, called T cells, that were trained to kill EBV-infected cells could affect these tumors, and in many patients it was found that giving these trained T cells caused a complete or partial response.

However, many patients do not have EBV in their lymphoma cells; therefore investigators now want to test whether it is possible to direct these special T cells against other types of proteins on the tumor cell surface with similar promising results. The proteins that will be targeted in this study are called tumor associated antigens (TAAs) - these are cell proteins that are specific to the cancer cell, so they either do not show or show up in low quantities on normal human cells.

In this study, we will target five TAAs which commonly show on lymphoma, called: NY-ESO-1, MAGEA4, PRAME, Survivin and SSX. This will be done by using special types of T cells called cytotoxic T lymphocytes (CTLs) generated in the lab.

In addition, some adult patients will receive a drug called azacytidine before giving the T cells. We hope that the combination helps the T cells work better.

The patient will give blood to make TAA-specific cytotoxic T cells in the lab. These cells will be grown and frozen. If the TAA-specific cytotoxic T cells can be made, the time from collection of the blood to manufacture of T cells for administration to the patient is about 1 to 2 months.

There are 4 stages of this study: an antigen-escalation phase, a dose-escalation stage, aza stage and pediatric patients stage.

The antigen-escalation phase will be first. Patients will receive TAA-specific T cells targeting first 1 and then 2 TAAs. Once this schedule proves safe, the next group of patients will receive TAA-specific T cells targeting first 2 and then 3 TAAs. This process will continue until all 4 levels are studied. This means that the final cohort of patients will receive TAA-specific T cells targeting first 4 and then 5 TAAs. If the side-effects are too severe, the number of TAAs being targeted will be lowered or the T cell injections will be stopped. Each patient will receive 2 infusions at the same dose 28 days apart

After the antigen-escalation phase, the dose-escalation phase will begin. Patients will be started on the lowest dose (1 of 3 different levels) of T cells. Once that dose schedule proves safe, the next group of patients will be started at a higher dose. This process will continue until all 3 dose levels are studied. If the side-effects are too severe, the dose will be lowered or the T cell injections will be stopped. Each patient will receive 2 infusions at the same dose 14 days apart

After the dose escalation stage, adult patients will be enrolled on the aza stage where they will receive the drug aza followed by two infusions of T cells on dose level 2. Patients will be given 3 cycles of aza (administered daily through a vein for 5 days, every 28 days) followed by 2 doses of multiTAA-specific T cells administered 14 days apart. Before the patient is given the aza they will be given a drug to help prevent nausea and vomiting.

On the pediatric stage, pediatric patients will receive 2 infusions of T cells on dose level 2. The T cells will be given 14 days apart.

The cells will be injected by IV over 10 minutes. The patients may be pre-treated with acetaminophen (Tylenol) and diphenhydramine (Benadryl). Acetaminophen (Tylenol) and diphenhydramine (Benadryl) are given to prevent a possible allergic reaction to the T cell administration. If after the second infusion there is a reduction in the size of the patient's lymphoma on CT or MRI scan as assessed by a radiologist, the patient can receive up to six (6) additional doses of the T cells at monthly intervals if they wish. All of the treatments will be given by the Center for Cell and Gene Therapy at Houston Methodist Hospital or Texas Children's Hospital.

In between the first and second T cell infusions and for 6 weeks after the last infusion, the patient should not receive any other anti-cancer treatments such as radiation therapy or chemotherapy. If the patient does receive any other therapies in-between the first and second infusion of T cells, they will be taken off treatment and will not be able to receive the second infusion of T cells.

MEDICAL TESTS BEFORE TREATMENT

• Physical exam.
• Blood tests to measure blood cells, kidney and liver function.
• Measurements of your tumor by routine imaging studies. We will use the imaging study that was used before to follow your tumor: CT, MRI, or PET.
• Pregnancy test if you are a female who can have children.

MEDICAL TESTS AFTER TREATMENT

- Imaging study 6 weeks after the 2nd TAA-CTL infusion.

To learn more about the way the T cells are working in the patient's body, an extra 20-40 mL (4-8 teaspoons) of blood will be taken before each cycle of aza (if applicable), 2 weeks after each cycle of aza (if applicable), before each T-cell infusion, and at Weeks 1, 2, 4 and 6. One additional blood sample might be drawn 3 to 4 days post the T-cell infusion; this is optional. Afterwards, blood will be collected at 3, 6, 9 and 12 months after the last infusion. The blood may be drawn from a central line at the time of the patient's regular blood tests. Investigators will use this blood to see how long the T cells last,and to look at the immune response to the patient's cancer.

Study Duration: Patients will be on active study participation for approximately one year. Patients who receive additional doses of the T cells as described above will be actively followed until 1 year after their last dose of T cells. Investigators will then remain in contact with patients once a year for up to 4 additional years (total of 5 years follow-up) in order to evaluate disease response long-term.

Inclusion Criteria:

PROCUREMENT:

1. Any patient regardless of sex, with a diagnosis of Hodgkin or non-Hodgkin lymphoma.
2. Life expectancy of 6 weeks or greater.
3. Hgb greater than or equal to 7.0
4. Patient and,or parent,guardian able to give informed consent.

TREATMENT:

1. Any patient regardless of sex, with a diagnosis of Hodgkin or non-Hodgkin lymphoma:

   Group A: Patients greater than or equal to 18 years old

   • with active disease:

     • in second or subsequent relapse.
     • in first relapse for indolent lymphoma after first-line therapy for relapse.
     • or first relapse if immunosuppressive chemotherapy contraindicated.
     • primary refractory disease or if persistent disease after first-line therapy of relapse.

   • or multiply relapsed patients in remission who are at a high risk of relapse.

   • or the lymphoma is a second malignancy e.g. a Richters transformation of CLL after failing front line therapy.

   OR

   Group B: Patients greater than or equal to 18 years old after autologous or syngeneic SCT (as adjuvant therapy).

   OR

   Group C: azacytidine plus multiTAA-T cells Patients greater than or equal to 18 years old

   • with active disease in:

     • second or subsequent relapse
     • first relapse for indolent lymphoma after first line therapy for relapse
     • first relapse if immunosuppressive chemotherapy contraindicated

   • with primary refractory disease or persistent disease after first line therapy of relapse

   • or lymphoma as a second malignancy e.g. a Richters transformation of CLL after failing front line therapy

   OR

   GROUP D: Patients less than 18 yrs old

   • with active disease in:

     • second or subsequent relapse
     • first relapse for indolent lymphoma after first line therapy for relapse
     • first relapse if immunosuppressive chemotherapy contraindicated

   • with primary refractory disease or persistent disease after first line therapy of relapse

   • with lymphoma as a second malignancy e.g. a Richters transformation of CLL after failing front line therapy

2. Life expectancy of 6 weeks or greater.

3. Pulse oximetry of more than 95 percent on room air in patients who previously received radiation therapy.

4. Karnofsky,Lansky score of 50 or greater.

5. Creatinine 2X or less of upper limit of normal for age.

6. Patients should have been off other investigational therapy for one month prior to entry in this study.

7. Patients should have been off conventional therapy for at least 1 week prior to entry in this study, including rituximab.

8. Patient and,or parent,guardian able to give informed consent.

9. Due to unknown effects of this therapy on a fetus, pregnant women are excluded from this research. The male partner should use a condom. Females of child-bearing potential should use of at least two forms of contraception unless female has had a hysterectomy or tubal ligation.

10. Bilirubin 2X or less of upper limit of normal, AST 3X or less than the upper limit of normal, and Hgb greater than or equal to 7.0

    GROUP C (aza) Only:

11. Platelets greater than 25,000

Exclusion Criteria:

PROCUREMENT:

1. Patients with severe intercurrent infection.
2. Patients with active HIV infection at time of procurement (can be pending at the time of blood draw).
3. Patients receiving systemic corticosteroids.

TREATMENT:

1. Patients with severe intercurrent infection.

2. Patients receiving systemic corticosteroids.

3. Pregnant breastfeeding.

4. Active viral infection with HIV or hepatitis type B or C. "Active" infection defined as infectious disease testing indicating that patient blood is reactive for Hep B, C and/or HIV and confirmed using PCR to measure viral load.

   GROUP C (aza) Only:

5. Abnormal coagulation parameters (PT greater than 15 seconds, PTT greater than 40 seconds, and/or INR greater than 1.5)

6. Significant active cardiac disease within the previous 6 months including:

   1. NYHA class 4 CHF
   2. Unstable angina
   3. Myocardial infarction

7. Known or suspected hypersensitivity to azacitidine or mannitol

8. Patients with advanced malignant hepatic tumors.