LMP-specific T-cells for Patients With Relapsed EBV-positive Lymphoma (ALCI)

• Safety of 2 intravenous injections of autologous or allogeneic LMP-specific cytotoxic T-lymphocytes (CTL) in patients with relapsed Hodgkin's or non-Hodgkin's lymphoma. [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
• To determine the survival and the immune function of LMP-specific cytotoxic T-lymphocyte lines. [ Time Frame: 5 years ] [ Designated as safety issue: No ]
• To assess the anti-viral and anti-tumor effects of LMP-specific CTL. [ Time Frame: 5 yearas ] [ Designated as safety issue: No ]
• To obtain preliminary information on the safety and response to an extended dosage regimen [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]

Patients have a type of lymph gland disease called Hodgkin or non-Hodgkin Lymphoma or Lymphoepithelioma or severe chronic active EBV (SCAEBV) or leiomyosarcoma which has come back or may come back or has not gone away after treatment, including the best treatment we know for these diseases. We are asking patients to volunteer to be in a research study using special immune system cells called LMP- specific cytotoxic T lymphocytes, a new experimental therapy.

Some patients with Lymphoma or SCAEBV or leiomyosarcoma show evidence of infection with the virus that causes infectious mononucleosis Epstein Barr virus (EBV) before or at the time of their diagnosis. EBV is found in the cancer cells of up to half the patients with Hodgkin's and non-Hodgkin Lymphoma, suggesting that it may play a role in causing Lymphoma. The cancer cells (in lymphoma) and some B cells (in SCAEBV) infected by EBV are able to hide from the body's immune system and escape destruction. We want to see if special white blood cells, called T cells, that have been trained to kill EBV infected cells can survive in the blood and affect the tumor.

We have used this sort of therapy to treat a different type of cancer that occurs after bone marrow or solid organ transplant called post transplant lymphoma. In this type of cancer the tumor cells have 9 proteins made by EBV on their surface. We grew T cells in the laboratory that recognized all 9 proteins and were able to successfully prevent and treat post transplant lymphoma. However in Hodgkin disease and non-Hodgkin Lymphoma and SCAEBV, the tumor cells and B cells only express 2 EBV proteins. In a previous study we made T cells that recognized all 9 proteins and gave them to patients with Hodgkin disease. Some patients had a partial response to this therapy but no patients had a complete response. We think one reason may be that many of the T cells reacted with proteins that were not on the tumor cells. In this present study we are trying to find out if we can improve this treatment by growing T cells that recognize proteins expressed on EBV infected Lymphoma cells and B cells called LMP-1 and LMP2. These special T cells are called LMP-specific cytotoxic T-lymphocytes (CTLs). These LMP-specific cytotoxic T cells are an investigational product not approved by the Food and Drug Administration.

We will first test a biopsy of the tumor or lymph node that has already been done to see if the tumor or tissue cells are EBV positive. If the patient is eligible, we will then take 60 of blood from the patient or their donor on one or two occasions. We will use this blood to grow T cells. We will first grow special type of cells called dendritic cells or monocytes which will stimulate the T cells and we will put a specially produced human viruses that carries the LMP genes into the dendritic cells or monocytes. They will then be used to stimulate T cells. This stimulation will train the T cells to kill cells with LMP on their surface. We will then grow these LMP specific CTLs by more stimulation with EBV infected cells. 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 LMP on their surface. If the counts are low we may need to obtain additional blood samples to make these cells.

Prior to giving the patient the CTLs we will test the cells to make sure they don't attack the tissue.

The cells will then be thawed and injected into the patient over 10 minutes, after pretreatment with Tylenol and Benadryl. Tylenol and Benadryl are given to prevent a possible allergic reaction to the T cell administration. Initially, two doses of T cells will be given two weeks apart. If after the second infusion there is a reduction in the size of the lymphoma on CT or MRI scan as assessed by a radiologist, the patient can receive up to six additional doses of the T cells if the patient wishes. This is a dose escalation study which means that for some patients the second dose may be larger than the first. All of the treatments will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital or the Methodist Hospital.

We will follow the patient after the injections. The patient will either be seen in the clinic or they will be contacted by a research nurse yearly for 5 years. To learn more about the way the T cells are working in the body, an extra 20-40 mls of blood will be taken before each infusion and then 4 hours after each infusion(optional), 3-4 days after each infusion (optional) and then weekly for 2 weeks after each infusion (total of 9 times). Two weeks after the last infusion, blood will then be taken again and then every 3 months for 1 year, then once a year for 5 years. We will use this blood to see how long the T cells last and to look at the immune response to the cancer.

• Hodgkin Disease
• Non Hodgkin Lymphoma

• Biological: Injection of LMP Specific Cytotoxic T-Lymphocytes (group 1)

  Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:

  Day 0 2 x 10e7 cells/m2 Day 14 2 x 10e7 cells/m2

• Biological: Injection of LMP Specific Cytotoxic T-Lymphocytes (group 2)

  Group Two:

  Day 0 2 x 107 cells/m2 Day 14 1 x 108 cells/m2 2 injections, 14 days apart

• Biological: Injection of LMP Specific Cytotoxic T-Lymphocytes (group 3)
  Day 0 1 x 108 cells/m2 Day 14 2 x 108 cells/m2 2 injections, 14 days apart

• Experimental: A
  Patients receiving CTLs as therapy for relapsed Lymphoma/Lymphoepithelioma or who are at high risk for relapse
  Interventions:

  • Biological: Injection of LMP Specific Cytotoxic T-Lymphocytes (group 1)
  • Biological: Injection of LMP Specific Cytotoxic T-Lymphocytes (group 2)
  • Biological: Injection of LMP Specific Cytotoxic T-Lymphocytes (group 3)
• Experimental: B
  Patients receiving CTLs as adjunctive therapy following autologous or syngeneic transplant
  Interventions:

  • Biological: Injection of LMP Specific Cytotoxic T-Lymphocytes (group 1)
  • Biological: Injection of LMP Specific Cytotoxic T-Lymphocytes (group 2)
  • Biological: Injection of LMP Specific Cytotoxic T-Lymphocytes (group 3)
• Experimental: C
  Patients receiving CTLs following allogeneic stem cell transplant
  Interventions:

  • Biological: Injection of LMP Specific Cytotoxic T-Lymphocytes (group 1)
  • Biological: Injection of LMP Specific Cytotoxic T-Lymphocytes (group 2)
  • Biological: Injection of LMP Specific Cytotoxic T-Lymphocytes (group 3)

• Cohen JI, Jaffe ES, Dale JK, Pittaluga S, Heslop HE, Rooney CM, Gottschalk S, Bollard CM, Rao VK, Marques A, Burbelo PD, Turk SP, Fulton R, Wayne AS, Little RF, Cairo MS, El-Mallawany NK, Fowler D, Sportes C, Bishop MR, Wilson W, Straus SE. Characterization and treatment of chronic active Epstein-Barr virus disease: a 28-year experience in the United States. Blood. 2011 Jun 2;117(22):5835-49. Epub 2011 Mar 31.
• Fox CP, Haigh TA, Taylor GS, Long HM, Lee SP, Shannon-Lowe C, O'Connor S, Bollard CM, Iqbal J, Chan WC, Rickinson AB, Bell AI, Rowe M. A novel latent membrane 2 transcript expressed in Epstein-Barr virus-positive NK- and T-cell lymphoproliferative disease encodes a target for cellular immunotherapy. Blood. 2010 Nov 11;116(19):3695-704. Epub 2010 Jul 29.
• Bollard CM, Gottschalk S, Leen AM, Weiss H, Straathof KC, Carrum G, Khalil M, Wu MF, Huls MH, Chang CC, Gresik MV, Gee AP, Brenner MK, Rooney CM, Heslop HE. Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer. Blood. 2007 Oct 15;110(8):2838-45. Epub 2007 Jul 3.

INCLUSION CRITERIA:

1. Any patient, regardless of age or sex, with EBV-positive Hodgkin's or non-Hodgkin's Lymphoma, or lymphoepithelioma or leiomyosarcoma regardless of the histological subtype or EBV (associated)-T/NK-lymphoproliferative disease or Severe Chronic EBV*

   a - In second or subsequent relapse (or first relapse or with active disease if immunosuppressive chemotherapy contraindicated or multiply relapsed patients currently in remission who have a high risk of relapse) OR with primary disease or in first remission if immunosuppressive chemotherapy is contraindicated, e.g. patients who develop Hodgkin disease after solid organ transplantation or if the Lymphoma is a second malignancy e.g. a Richters transformation of CLL.(Group A)

   OR

   b - In remission or with minimal residual disease status after autologous or syngeneic SCT for Hodgkin's or non-Hodgkin's Lymphoma/Lymphoepithelioma/SCAEBV. (Group B)

   OR

   c - Patients after allogeneic SCT for Hodgkin's Lymphoma or Non-Hodgkin's Lymphoma/Lymphoepithelioma/SCAEBV. (Group C)

2. Patients with life expectancy 6 weeks or greater.
3. Tumor tissue EBV positive
4. Patients with a Karnofsky/Lansky score of 50 or greater
5. Donor HIV negative (if autologous product - patient must be HIV negative)
6. If post allogeneic SCT must not have less than 50% donor chimerism in either peripheral blood or bone marrow
7. Patients with bilirubin 3x normal or less, AST 5x normal or less, and Hgb greater than 8.0
8. Patients with a creatinine 2x normal or less for age
9. Patients should have been off other investigational therapy for one month prior to entry in this study.

10. Patient, parent/guardian able to give informed consent.

    • SCAEBV is defined as patients with high EBV viral load in plasma or PBMC (>4000 genomes per ug PBMC DNA) and/or biopsy tissue positive for EBV

EXCLUSION CRITERIA:

1. Patients with a severe intercurrent infection.
2. Donors who are HIV positive or Patients who are HIV positive if autologous product to be used
3. Patients with greater than Grade II GVHD
4. Due to unknown effects of this therapy on a fetus, pregnant women are excluded from this research. The male partner should use a condom.

Note: Patients who would be excluded from the protocol strictly for laboratory abnormalities can be included at the investigator's discretion after approval by the CCGT Protocol Review Committee. Any desired variance from the entry criteria will be discussed with the IRB and reported annually to the FDA.

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