LMP-specific T-cells for Patients With Relapsed EBV-positive Lymphoma
Condition: Hodgkin Disease; Non Hodgkin Lymphoma; Lymphoepithelioma; Leiomyosarcoma
MeSH terms: Lymphoma; Hodgkin Disease; Leiomyosarcoma
Intervention: LMP1/2 CTLs (ALCI - Group A); LMP1/2 CTLs (ALCI - Group B); LMP1/2 CTLs (ALCI - Group C); LMP2 CTLs (ALSCER - Group A); LMP2 CTLs (ALSCER - Group B); LMP2 CTLs (ALSCER - Group C); LMP1/2 CTLs (ALCI - Expansion - Group A); LMP1/2 CTLs (ALCI - Expansion Group B); LMP1/2 CTLs (ALCI - Expansion Group C)
Intervention description: Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:
Dose Level One
Day 0: 2 x 10^7 cells/m2; Day 14: 2 x 10^7 cells/m2
Dose Level Two
Day 0: 2x10^7 cells/m2; Day 14: 1x10^8 cells/m2
Dose Level Three
Day 0: 1x10^8 cells/m2; Day 14: 2x10^8 cells/m2; Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:
Dose Level One
Day 0: 2x10^7 cells/m2; Day 14: 2x10^7 cells/m2
Dose Level Two
Day 0: 2x10^7 cells/m2; Day 14: 1x10^8 cells/m2
Dose Level Three
Day 0: 1x10^8 cells/m2; Day 14: 2x10^8 cells/m2; Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:
Dose Level One
Day 0: 2x10^7 cells/m2; Day 14: 2x10^7 cells/m2
Dose Level Two
Day 0: 2x10^7 cells/m2; Day 14: 1x10^8 cells/m2
Dose Level Three
Day 0: 1x10^8 cells/m2; Day 14: 2x10^8 cells/m2; Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:
Dose Level One
Day 0: 2 x 10^7 cells/m2; Day 14: 2 x 10^7 cells/m2
Dose Level Two
Day 0: 2x10^7 cells/m2; Day 14: 1x10^8 cells/m2
Dose Level Three
Day 0: 1x10^8 cells/m2; Day 14: 2x10^8 cells/m2; Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:
Dose Level One
Day 0: 2x10^7 cells/m2; Day 14: 2x10^7 cells/m2
Dose Level Two
Day 0: 2x10^7 cells/m2; Day 14: 1x10^8 cells/m2
Dose Level Three
Day 0: 1x10^8 cells/m2; Day 14: 2x10^8 cells/m2; Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:
Dose Level One
Day 0: 2x10^7 cells/m2; Day 14: 2x10^7 cells/m2
Dose Level Two
Day 0: 2x10^7 cells/m2; Day 14: 1x10^8 cells/m2
Dose Level Three
Day 0: 1x10^8 cells/m2; Day 14: 2x10^8 cells/m2; Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:
Dose Level One
Day 0: 2 x 10^7 cells/m2; Day 14: 2 x 10^7 cells/m2; Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:
Dose Level One
Day 0: 2x10^7 cells/m2; Day 14: 2x10^7 cells/m2; Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:
Dose Level One
Day 0: 2x10^7 cells/m2; Day 14: 2x10^7 cells/m2
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 74.0
Sex: All
Healthy volunteers: No
Keywords: Lymphoma; EBV-T/NK lymphoproliferative disease; Severe Chronic EBV; LMP1/2; CTL; EBV; Relapse; LMP2A

Summary:

      This protocol is broken up into 2 portions to determine the maximum tolerated dose for
      treating patients with a type of lymph gland disease.

      The 1st portion, called ALASCER are for people with a type of lymph gland cancer called
      Hodgkin or non-Hodgkin Lymphoma or Lymphoepithelioma which has returned or may return or has
      not gone away after treatment, including the best treatment we know for Lymphoma. While the
      2nd portion (ALCI) also includes Lymphoepithelioma, severe chronic active EBV (SCAEBC), and
      leiomyosarcoma.

      Some patients with Lymphoma 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. Investigators want to see if special white blood cells, called T cells,
      that have been trained to kill EBV infected cells can survive in your blood and affect the
      tumor.

      The investigators 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. The
      investigators 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. Investigators 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 only recognize one of
      the proteins expressed on infected EBV Lymphoma cells called LMP-2a, and B cells called LMP1
      and LMP2. These special T cells are called LMP specific cytotoxic T-lymphocytes (CTLs).

      The purpose of the study is to find the largest safe dose of LMP specific cytotoxic T cells,
      to learn what the side effects are and to see whether this therapy might help patients with
      Hodgkin disease, non-Hodgkin Lymphoma, Lymphoepithelioma, SCAEBV or leiomyosarcoma.
    

Eligibility criteria:

        ALASCER (Part 1 of Study)

        INCLUSION CRITERIA

          1. Any patient, regardless of age or sex, with EBV-positive Lymphoma, or
             lymphoepithelioma regardless of the histological subtype or EBV (associated)-T/NK-LPD.

             In second or subsequent relapse (or first relapse or with active disease if
             immunosuppressive chemotherapy contraindicated or multiply relapsed patients in
             remission who have a high risk of relapse) OR any patient 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 In remission or
             with minimal residual disease status after autologous or syngeneic SCT for Hodgkin's
             or non-Hodgkin's Lymphoma or lymphoepithelioma. (Group B) OR In remission or with
             detectable disease after allogeneic SCT. (Group C)

          2. Patients with life expectancy > 6 weeks.

          3. Patients with a Karnofsky/Lansky score of > 50

          4. No severe intercurrent infection.

          5. Donor HIV negative (if autologous product - patient must be HIV negative)

          6. No evidence of GVHD > Grade II at time of enrollment.

          7. If post allogeneic SCT must not have less than 50% donor chimerism in either
             peripheral blood or bone marrow

          8. Patient, parent/guardian able to give informed consent.

          9. Patients with bilirubin <3x normal, AST <5x normal, and Hgb >8.0 (see Section 7.2).

         10. Patients with a creatinine <2x normal for age

         11. Patients should have been off other investigational therapy for one month prior to
             entry in this study.

        EXCLUSION CRITERIA

          1. Patients with a life expectancy of <6 weeks.

          2. Patients with a Karnofsky/Lansky score of < 50.

          3. Patients with a severe intercurrent infection.

          4. Patients with bilirubin >3x normal. AST >5x normal or abnormal prothrombin time.

          5. Patients with a creatinine >2x normal for age

          6. Donors who are HIV positive (Patients who are HIV positive - if autologous product)

          7. Patients with GVHD Grades III-IV

          8. 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 and the FDA reviewer.

        ALCI and ALCI Expansion (Part 2 of Study)

        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#

             (#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)

             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 or
             subsequent 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 in remission or with detectable disease after allogeneic SCT. (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.

        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.