Autologous/Allogeneic TGFbeta-resistant LMP-specific CTL, Lymphoma (TGF-beta)
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Lymphoma |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 10/26/2018 |
| Start Date: | April 2006 |
| End Date: | July 2031 |
Administration of TGF-b Resistant LMP-Specific Cytotoxic T-Lymphocytes to Patients With Relapsed EBV-Positive Lymphoma
Patients have a type of lymph gland cancer called HD, NHL or lymphoepithelioma (these 3
diseases will be referred to as "Lymphoma"). The lymphoma has come back or has not gone away
after treatment. This is a research study using special immune system cells called
TGFb-resistant LMP-specific cytotoxic T lymphocytes (DNR-CTL), a new experimental therapy.
Some patients with Lymphoma show signs of infection with the Epstein Barr virus (EBV) before
or at the time of their Lymphoma diagnosis. EBV is found in the cancer cells of up to 1/2 the
patients with Lymphoma, suggesting 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). The investigators want
to see if special white blood cells (called T cells) that have been given a gene that they
hope will let them survive against TGFb and that have been trained to kill EBV infected cells
can also survive in the blood and kill the tumor.
Investigators 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 they were able to successfully prevent and treat
post transplant lymphoma. However when they used a similar approach in HD some patients had a
partial response to this therapy, but no patients had a complete response. In a follow-up
study they tried to find out if they could improve this treatment by growing T cells that
recognize 2 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 those who had a lot of disease. Investigators
think that a reason for this is that the tumor cells are releasing TGFb. For this reason,
they want to find out if they can make the CTL resistant to TGFb by putting in a new gene
called TGFb resistance gene. Investigators hope that this will improve this treatment for
relapsed lymphoma. These TGFb-resistant LMP-specific CTLs are an investigational product not
approved by FDA.
The purpose of this study is to find the largest safe dose of TGFb resistant LMP-specific
CTLs, to learn what the side effects are and to see whether this therapy might help patients
with Lymphoma.
diseases will be referred to as "Lymphoma"). The lymphoma has come back or has not gone away
after treatment. This is a research study using special immune system cells called
TGFb-resistant LMP-specific cytotoxic T lymphocytes (DNR-CTL), a new experimental therapy.
Some patients with Lymphoma show signs of infection with the Epstein Barr virus (EBV) before
or at the time of their Lymphoma diagnosis. EBV is found in the cancer cells of up to 1/2 the
patients with Lymphoma, suggesting 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). The investigators want
to see if special white blood cells (called T cells) that have been given a gene that they
hope will let them survive against TGFb and that have been trained to kill EBV infected cells
can also survive in the blood and kill the tumor.
Investigators 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 they were able to successfully prevent and treat
post transplant lymphoma. However when they used a similar approach in HD some patients had a
partial response to this therapy, but no patients had a complete response. In a follow-up
study they tried to find out if they could improve this treatment by growing T cells that
recognize 2 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 those who had a lot of disease. Investigators
think that a reason for this is that the tumor cells are releasing TGFb. For this reason,
they want to find out if they can make the CTL resistant to TGFb by putting in a new gene
called TGFb resistance gene. Investigators hope that this will improve this treatment for
relapsed lymphoma. These TGFb-resistant LMP-specific CTLs are an investigational product not
approved by FDA.
The purpose of this study is to find the largest safe dose of TGFb resistant LMP-specific
CTLs, to learn what the side effects are and to see whether this therapy might help patients
with Lymphoma.
Investigators will test 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. Then they will take some blood from the
donor, which is used to grow T cells. First they will grow a special type of cell called
dendritic cells (or monocytes), which stimulates the T cells and add 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. These dendritic cells
(or monocytes) are then used to stimulate T cells. The stimulation trains the T cells to kill
cells with LMP on their surface. Investigators will then make more LMP-specific CTLs by
stimulating them with EBV infected cells (which we will make from the subject's blood or the
donor's blood by infecting them with EBV in the laboratory). They also will put the
adenovirus that carries the LMP1 and LMP2 genes into these EBV infected cells so that they
increase the amount of LMP1 and LMP2, which these cells have.
These EBV infected cells are treated with radiation so they cannot grow. Once sufficient
numbers of T cells are made, investigators test them to see if they kill cells with LMP on
their surface. To make sure that these cells won't attack the subjects tissues they test the
cells against the skin cells or against T cells that they grow 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. Investigators used a mouse retrovirus that had been
changed to stop it from causing infection to add the mutant TGFb receptor to the cells.
WHAT THE INFUSION WILL BE LIKE:
After the cells are made, they will be 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.
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 investigators don't know what the highest dose of T cells
with the new gene is safe. To find out, they will give the cells to 2 participants at one
dose level. If that is safe they 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.
All of the Treatments will be given by the Center for Cell and Gene Therapy at Texas
Children's Hospital or Houston Methodist Hospital.
FOLLOW-UP STUDIES We will follow the subject after the injections. Total time participation
for this study will be 15 years.
to see if the subject is eligible for this study. Then they will take some blood from the
donor, which is used to grow T cells. First they will grow a special type of cell called
dendritic cells (or monocytes), which stimulates the T cells and add 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. These dendritic cells
(or monocytes) are then used to stimulate T cells. The stimulation trains the T cells to kill
cells with LMP on their surface. Investigators will then make more LMP-specific CTLs by
stimulating them with EBV infected cells (which we will make from the subject's blood or the
donor's blood by infecting them with EBV in the laboratory). They also will put the
adenovirus that carries the LMP1 and LMP2 genes into these EBV infected cells so that they
increase the amount of LMP1 and LMP2, which these cells have.
These EBV infected cells are treated with radiation so they cannot grow. Once sufficient
numbers of T cells are made, investigators test them to see if they kill cells with LMP on
their surface. To make sure that these cells won't attack the subjects tissues they test the
cells against the skin cells or against T cells that they grow 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. Investigators used a mouse retrovirus that had been
changed to stop it from causing infection to add the mutant TGFb receptor to the cells.
WHAT THE INFUSION WILL BE LIKE:
After the cells are made, they will be 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.
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 investigators don't know what the highest dose of T cells
with the new gene is safe. To find out, they will give the cells to 2 participants at one
dose level. If that is safe they 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.
All of the Treatments will be given by the Center for Cell and Gene Therapy at Texas
Children's Hospital or Houston Methodist Hospital.
FOLLOW-UP STUDIES We will follow the subject after the injections. Total time participation
for this study will be 15 years.
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
all confirmed on any tissue sample.
Primary refractory lymphoma or in second or subsequent relapse including after
autologous or syngeneic stem cell transplant OR patients at a high risk for relapse
defined as: (i) patients with primary refractory lymphoma or multiply relapsed
lymphoma who are in remission but not eligible for autologous SCT or (ii) patients
with relapsed lymphoma after autologous SCT who are in remission but not eligible for
allogeneic SCT (Group A)
OR
Any patient who has received an allogeneic SCT for EBV Lymphoma or EBV
(associated)-T/NK-LPD or Lymphoepithelioma (Group B)
2. Patients with life expectancy 6 weeks or greater from the time of CTL infusion.
3. Patients with a Karnofsky score of 50 or greater.
4. If post allogeneic SCT must not have less than 50% donor chimerism in either
peripheral blood or bone marrow
5. Patients with bilirubin 3x normal or less, AST 5x normal or less, and Hgb greater than
8.0
6. Patients with a creatinine 2x normal for age or less
7. Patients with O2 saturations greater than 93% on room air (measured by pulse oximetry)
8. Patient, parent/guardian able to give informed consent.
9. Patients should have been off other investigational therapy for one month prior to
entry in this study.
EXCLUSION CRITERIA:
1. Patients with a severe intercurrent infection.
2. Patients with evidence of GVHD greater than Grade II at time of enrollment.
3. HIV positive at time of procurement cells for CTL generation
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.
We found this trial at
2
sites
Texas Children's Hospital Texas Children's Hospital, located in Houston, Texas, is a not-for-profit organization whose...
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Houston Methodist Hospital Houston Methodist is comprised of a leading academic medical center in the...
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