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

This study is currently recruiting participants.
Verified July 2013 by Baylor College of Medicine
Sponsor:
Collaborators:
Texas Children's Hospital
The Methodist Hospital System
Center for Cell and Gene Therapy, Baylor College of Medicine
Information provided by (Responsible Party):
Helen Heslop, Baylor College of Medicine
ClinicalTrials.gov Identifier:
NCT00062868
First received: June 17, 2003
Last updated: July 25, 2013
Last verified: July 2013
  Purpose

Patients have a type of lymph gland disease (HD or NHL, Lymphoepithelioma, 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 known for these diseases. This research study uses 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 NHL, 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 the 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 lab that recognized all 9 proteins and were able to successfully prevent and treat post transplant lymphoma. However, in HD and NHL and SCAEBV, the tumor cells and B cells only express 2 EBV proteins. In a previous study, T cells were made that recognized all 9 proteins and were given to patients with HD. Some patients had a partial response to this therapy but no patients had a complete response. The investigators think one reason may be that many of the T cells reacted with proteins that were not on the tumor cells. In this study, they are trying to find out if they 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 FDA.

The purpose of this 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 HD, NHL, Lymphoepithelioma, SCAEBV or leiomyosarcoma.


Condition Intervention Phase
Hodgkin Disease
Non Hodgkin Lymphoma
Lymphoepithelioma
Leiomyosarcoma
Biological: LMP1/2 CTLs (Group A)
Biological: LMP1/2 CTLs (Group B)
Biological: LMP1/2 CTLs (Group C)
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Administration of LMP-Specific Cytotoxic T-Lymphocytes to Patients With Relapsed EBV-Positive Lymphoma (ALCI)

Resource links provided by NLM:


Further study details as provided by Baylor College of Medicine:

Primary Outcome Measures:
  • Number of patients with dose limiting toxicity (DLT) [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
    Toxicity will be evaluated according to NCI Common Terminology Criteria for Adverse Events scale, version 2.0. DLT will be defined as development of Grade III-IV GVHD or any toxicity that is irreversible, life threatening or Grade 3-4 considered to be primarily related to the CTL injection.


Secondary Outcome Measures:
  • Survival and Immune Function of LMP-specific CTLs [ Time Frame: 6 years ] [ Designated as safety issue: No ]
    Survival and function will be measured by frequencies and immunological parameters from ELISPOT function assays.

  • Frequencies of anti-viral load and anti-tumor effects [ Time Frame: 6 years ] [ Designated as safety issue: No ]
    Frequencies will be measured by PCR EBV DNA measurements over the follow-up period and summarized using descriptive statistics. Growth curves of measurements over time within a patient will be be made to visualize general patterns of immune response.

  • Frequencies of patients with Tumor Response of extended dosage regimen [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
    Comparison of diagnostic imaging studies from pre-infusion to 6 weeks after the second infusion will be summarized. Frequencies and proportions of responders will be summarized overall and by dose levels if there are enough patients per dose level.


Estimated Enrollment: 89
Study Start Date: April 2007
Estimated Study Completion Date: April 2018
Estimated Primary Completion Date: April 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LMP1/2 CTLs (Group A)
Patients receiving CTLs as therapy for relapsed Lymphoma/Lymphoepithelioma/leiomyosarcoma or who are at risk for relapse
Biological: LMP1/2 CTLs (Group A)

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

Experimental: LMP1/2 CTLs (Group B)
Patients receiving CTLs as adjunctive therapy following autologous or syngeneic transplant.
Biological: LMP1/2 CTLs (Group B)

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

Experimental: LMP1/2 CTLs (Group C)
Patients receiving CTLs following allogeneic stem cell transplant.
Biological: LMP1/2 CTLs (Group C)

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


Detailed Description:

Investigators 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, investigators will then take 60 mL (about 12 teaspoons) of blood from the patient or their donor on one or two occasions. They will use this blood to grow T cells. First they will grow a special type of cells called dendritic cells or monocytes which will stimulate the T cells. Next they will put a specially produced human virus 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. Investigators 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 sufficient numbers of T cells have been made, investigators will test them to make sure they kill cells with LMP on their surface. If the counts are low they may need to obtain additional blood samples to make these cells. Prior to giving the patient the CTLs, the cells will be tested to make sure they don't attack the tissue.

The cells will then be thawed and injected into the patient over 10 minutes. 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.

For follow-up after the CTL infusions, the patient will be seen every 3 months for the first year. Then the patient will either be seen in the clinic or they will be contacted by a research nurse yearly for 5 years.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 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.

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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00062868

Contacts
Contact: Helen E Heslop, MD 832-824-4662 hheslop@bcm.edu
Contact: Vicky Torrano 832-824-7821 vxtorran@txch.org

Locations
United States, Texas
The Methodist Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Helen E Heslop, MD    832-824-4662    hheslop@bcm.edu   
Contact: Vicky Torrano    832-824-7821    vxtorran@txch.org   
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Helen E Heslop, MD    832-824-4662    hheslop@bcm.edu   
Contact: Vicky Torrano    832-824-7821    vxtorran@txch.org   
Sponsors and Collaborators
Baylor College of Medicine
Texas Children's Hospital
The Methodist Hospital System
Center for Cell and Gene Therapy, Baylor College of Medicine
Investigators
Principal Investigator: Helen E Heslop, MD Center for Cell and Gene Therapy, Baylor College of Medicine
  More Information

No publications provided by Baylor College of Medicine

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Helen Heslop, Professor, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT00062868     History of Changes
Obsolete Identifiers: NCT00070226, NCT00671164
Other Study ID Numbers: 9936-ALCI, ALCI
Study First Received: June 17, 2003
Last Updated: July 25, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Baylor College of Medicine:
Lymphoma
EBV-T/NK lymphoproliferative disease
Severe Chronic EBV
LMP1/2
CTL
EBV
Relapse

Additional relevant MeSH terms:
Hodgkin Disease
Leiomyosarcoma
Lymphoma
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Muscle Tissue
Neoplasms, Connective and Soft Tissue
Sarcoma

ClinicalTrials.gov processed this record on April 17, 2014