LMP2a-Specific Cytotoxic T-Lymphocytes Following CD45 Antibody for Lymphoma - Full Text View

Sponsor:	Baylor College of Medicine
Collaborators:	The Methodist Hospital System Texas Children's Hospital Center for Cell and Gene Therapy, Baylor College of Medicine
Information provided by:	Baylor College of Medicine
ClinicalTrials.gov Identifier:	NCT00082225

Purpose

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).
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 the investigators 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. The investigators 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, the investigators 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.

The investigators 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.

Condition	Intervention	Phase
LYMPHOMA	Biological: CD45 antibodies Biological: EBV specific T cells	Phase I

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Administration of LMP2a-Specific Cytotoxic T-Lymphocytes Following CD45 Antibody to Patients With Relapsed EBV-Positive Hodgkin's or Non-Hodgkin's Lymphoma

Resource links provided by NLM:

MedlinePlus related topics: Cancer Hodgkin Disease Lymphoma

Drug Information available for: Immunoglobulins Globulin, Immune

U.S. FDA Resources

Further study details as provided by Baylor College of Medicine:

Primary Outcome Measures:

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 ]

Enrollment:	4
Study Start Date:	October 2003
Estimated Study Completion Date:	April 2012
Primary Completion Date:	June 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 1 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	Biological: CD45 antibodies The antibody solution is administered by a syringe pump in incremental doses, 0.2-0.8 mg in the first hour and up to 10 mg/hr thereafter, for a maximum infusion time of 8 hrs. Biological: EBV specific T cells The following dose levels will be evaluated: Each patient will receive 1 injection, according to the following dosing schedules: 2 x 10e7 cells/m2 5 x 10e7 cells/m2 1 x 10e8 cells/m2
Experimental: 2 Patients receiving CTLs following allogeneic stem cell transplant	Biological: CD45 antibodies The antibody solution is administered by a syringe pump in incremental doses, 0.2-0.8 mg in the first hour and up to 10 mg/hr thereafter, for a maximum infusion time of 8 hrs. Biological: EBV specific T cells The following dose levels will be evaluated: Each patient will receive 1 injection, according to the following dosing schedules: 2 x 10e7 cells/m2 5 x 10e7 cells/m2 1 x 10e8 cells/m2

Arms

Assigned Interventions

Experimental: 1

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

Biological: CD45 antibodies

The antibody solution is administered by a syringe pump in incremental doses, 0.2-0.8 mg in the first hour and up to 10 mg/hr thereafter, for a maximum infusion time of 8 hrs.

Biological: EBV specific T cells

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

2 x 10e7 cells/m2 5 x 10e7 cells/m2

1 x 10e8 cells/m2

Experimental: 2

Patients receiving CTLs following allogeneic stem cell transplant

Biological: CD45 antibodies

The antibody solution is administered by a syringe pump in incremental doses, 0.2-0.8 mg in the first hour and up to 10 mg/hr thereafter, for a maximum infusion time of 8 hrs.

Biological: EBV specific T cells

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

2 x 10e7 cells/m2 5 x 10e7 cells/m2

1 x 10e8 cells/m2

Detailed Description:

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

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

Eligibility

Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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
Donor must HIV negative (if autologous product used - patient must be 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
No evidence of GVHD >Grade II at time of enrollment
Female patients with reproductive capacity must have a negative pregnancy test

Exclusion Criteria:

Patient, parent/guardian unable or unwilling to give informed consent
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
GVHD greater than Grade II at time of enrollment
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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00082225

Locations

United States, Texas
Texas Children's Hospital
Houston, Texas, United States, 77030
The Methodist Hospital
Houston, Texas, United States, 77030
Baylor College of Medicine
Houston, Texas, United States, 77030

Sponsors and Collaborators

Baylor College of Medicine

The Methodist Hospital System

Texas Children's Hospital

Center for Cell and Gene Therapy, Baylor College of Medicine

Investigators

Study Chair:

Malcolm K Brenner, MD

Baylor College of Medicine

More Information

No publications provided

Responsible Party:	Helen Heslop, MD, Baylor College of Medicine
ClinicalTrials.gov Identifier:	NCT00082225 History of Changes
Other Study ID Numbers:	14424-ACDAL, ACDAL
Study First Received:	May 3, 2004
Last Updated:	July 15, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by Baylor College of Medicine:

HODGKINS
NON-HODGKINS
LYMPHOMA

Additional relevant MeSH terms:

Lymphoma
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders

Immune System Diseases
Antibodies
Immunoglobulins
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on February 12, 2012