Safety Study of Injections of Autologous/Allogeneic TGFbeta-resistant LMP2A-specific Cytotoxic T-lymphocytes (CTL) (TGF-beta)
|First Received Date ICMJE||August 22, 2006|
|Last Updated Date||August 29, 2012|
|Start Date ICMJE||April 2006|
|Estimated Primary Completion Date||December 2015 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Safety and MTD of 2 IV injections of autologous/syngeneic or allogeneic TGFb resistant LMP2A-specific cytotoxic T-lymphocytes. [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]|
|Original Primary Outcome Measures ICMJE
|Change History||Complete list of historical versions of study NCT00368082 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Safety Study of Injections of Autologous/Allogeneic TGFbeta-resistant LMP2A-specific Cytotoxic T-lymphocytes (CTL)|
|Official Title ICMJE||Administration of TGF-b Resistant LMP2A-Specific Cytotoxic T-Lymphocytes to Patients With Relapsed EBV-Positive Lymphoma|
Patients have a type of lymph gland cancer called Hodgkin Disease, non-Hodgkin Lymphoma or lymphoepithelioma (these 3 diseases will be referred to as "Lymphoma"). The lymphoma has come back or has not gone away after treatment (including the best treatment we know for these cancers).
We are asking patients to volunteer to be in a research study using special immune system cells called TGFb-resistant LMP-specific cytotoxic T lymphocytes (DNR-CTL), a new experimental therapy. Patients may have already thought a lot about being in this study. They may even have already made a decision about whether to be in the study. Even if this is true for the patient, it is important that we give the patient this information and talk about it before we start them in the study.
Some patients with Lymphoma show signs of infection with the virus that causes infectious mononucleosis Epstein Barr virus (EBV) before or at the time of their diagnosis of the Lymphoma. EBV is found in the cancer cells of up to half the patients with Lymphoma, suggesting 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 by releasing a substance called Transforming Growth Factor-beta (TGFb). We want to see if special white blood cells (called T cells) that have been given a gene that we hope will let them survive against TGFb and that have been trained to kill EBV infected cells and can also survive in the blood and kill the tumor.
We have used this sort of therapy with specially trained T cells to treat a different type of cancer that occurs after bone marrow and solid organ transplant called post transplant lymphoma. In this type of cancer we were able to successfully prevent and treat post transplant lymphoma. However when we used a similar approach in Hodgkins disease some patients had a partial response to this therapy, but no patients had a complete response.
In a follow-up study we tried to find out if we could improve this treatment by growing T cells that recognize two of the proteins expressed on Lymphoma cells called LMP-1 and LMP2a. These special T cells were called LMP-specific cytotoxic T-lymphocytes (CTLs). Although some patients had tumor responses, CTL therapy alone did not cure patients who had a lot of disease. We think that a reason for this is that the tumor cells are releasing TGFb, which is a substance that inhibits the growth and function of CTLs. For this reason we want to find out if we can make the CTL resistant to TGFb by putting in a new gene called TGFb resistance gene. We hope but do not know that this will improve this treatment for relapsed lymphoma. These TGFb-resistant LMP-specific cytotoxic T lymphocytes are an investigational product not approved by the Food and Drug Administration.
We already tested a biopsy of the tumor to see if the tumor cells are EBV positive and to see if the subject is eligible for this study. We then took 60-70 ml (12 teaspoonfuls) of blood from the donor, which we then used to grow T cells. We first grew a special type of cell called dendritic cells (or monocytes), which stimulated the T cells and we added a specially produced human adenovirus that carries the LMP1 and LMP-2a genes into the dendritic cells(or monocytes). Addition of a gene to the cells is known as gene transfer. Adenoviruses are the types of viruses commonly found in the human respiratory system that can cause a respiratory infection. Respiratory illnesses caused by adenovirus infections range from the common cold to pneumonia. These dendritic cells (or monocytes) were then used to stimulate T cells. The stimulation trained the T cells to kill cells with LMP on their surface. We then made more LMP-specific CTLs by stimulating them with EBV infected cells (which we made from the subject's blood or the donor's blood by infecting them with EBV [called B95] in the laboratory). We also put the adenovirus that carries the LMP1 and LMP2 genes into these EBV infected cells so that we increase the amount of LMP1 and LMP2, which these cells have.
These EBV infected cells were treated with radiation so they cannot grow. Once we made sufficient numbers of T cells we tested them to see if they kill cells with LMP on their surface. To make sure that these cells won't attack the subjects tissues we tested the cells against the skin cells or against T cells that we grew in the laboratory.
To make these CTL resistant to the effects of the TGFb released by the tumor we put in a new gene called a mutant TGFb receptor. We used a mouse retrovirus that had been changed to stop it from causing infection to add the mutant TGFb receptor to the cells. Retroviruses differ from adenoviruses in that they enter the cell's DNA (genetic material) to make permanent changes to the cell.
WHAT THE INFUSION WILL BE LIKE:
After making these cells the cells were frozen. If the subject agrees to participate in this study, at the time they are scheduled to be treated, the cells will then be thawed and injected into the subject over 10 minutes. The subject may be pretreated with Tylenol (acetaminophen) and Benadryl (diphenhydramine). 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 subject's lymphoma (or no increase) on CT or MRI scans as assessed by a radiologist, the subject can receive up to six additional doses if it would be to their benefit, if they would like to receive more doses, and if there is enough product remaining to give them additional doses. This is a dose escalation study as we do not know what the highest dose of T cells with the new gene is safe. To find out we will give the cells to 2 participants at one dose level. If that is safe we will raise the dose given to the next group of participants. The dose the subject will get will depend on how many participants get the agent before and how they react. The investigator will tell the subject this information. This will help the subject think about possible harms and benefits. Since the treatment is experimental, what is likely to happen at any dose is not known.
All of the Treatments will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital or the Methodist Hospital.
FOLLOW-UP STUDIES We will follow the subject after the injections. Initially, at each visit about 10ml (2 teaspoonfuls) of blood will be taken every other week for 6 weeks after the first injection and then every 3 months for 1 year to monitor the blood chemistry and hematology. To learn more about the way the T cells are working in the body, an extra 20-50 mls (4-10 teaspoons) of blood will be taken before each infusion and then 2-4 hours after each infusion, 3-4 days after each infusion (optional depending on patient preference) and then weekly for 4 weeks and at weeks 6 and 8 after the first infusion. Blood will then be taken 4 weeks later and then every 3 months for 1 year, then once every 6 months for the first four years and then yearly thereafter for the next 10 years. Total time participation for this study will be 15 years.
We will use this blood to look for the frequency and activity of the cells that we have given; that is, to learn more about the way the T cells are working and how long they last in the body. We will also use this blood to see if there are any long-term side effects of putting the new gene (mutant TGFB receptor) into the cells. In addition to the blood draws, because you have received cells that have had a new gene put in them (DNR-CTL) the subject will need to have long term follow up for 15 years so we can see if there are any long term side effects of the gene transfer. Once a year the subject will be asked to have their blood drawn and answer questions about their general health and medical condition. The investigators may ask the subject to report any recent hospitalizations, new medications, or the development of conditions or illness that were not present when they enrolled in the study and may request that physical exams and/or laboratory tests be performed if necessary. We will also ask the subject to participate in the long-term follow-up phase if they leave the study early.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 1|
|Study Design ICMJE||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Intervention ICMJE||Genetic: TGF-b Resistant LMP2A-Specific Cytotoxic T-Lymphocytes
CTLs be given by intravenous injection over 1-10 minutes through either a peripheral or a central line. Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:
Day 0 2 x 107 cells/m2 Day 14 2 x 107 cells/m2
Day 0 6 x 107 cells/m2 Day 14 6 x 107 cells/m2
Day 0 1.5 x 108 cells/m2 Day 14 1.5 x 108 cells/m2
If patients with active disease have stable disease or a partial response at their 6 week or subsequent evaluations they will be eligible to receive up to 6 additional doses of CTLs at 1-2 monthly intervals-each of which will consist of the same cell number as their second injection.
Other Name: TGFbeta resistant LMP-specific CTLs
|Study Arm (s)||Experimental: TGFbeta resistant LMP-specific CTLs
Intervention: Genetic: TGF-b Resistant LMP2A-Specific Cytotoxic T-Lymphocytes
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE||20|
|Estimated Completion Date||December 2030|
|Estimated Primary Completion Date||December 2015 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Accepts Healthy Volunteers||No|
|Location Countries ICMJE||United States|
|NCT Number ICMJE||NCT00368082|
|Other Study ID Numbers ICMJE||17946-TGFBeta, TGF-beta|
|Has Data Monitoring Committee||Yes|
|Responsible Party||catherine bollard, Baylor College of Medicine|
|Study Sponsor ICMJE||Baylor College of Medicine|
|Information Provided By||Baylor College of Medicine|
|Verification Date||August 2012|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP