Administration of TGF-b Resistant LMP2A-Specific Cytotoxic T-Lymphocytes to Patients With Relapsed EBV-Positive Lymphoma
Investigators 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. Then they took 60-70 ml (12
teaspoonfuls) of blood from the donor, which then can be used to grow T cells. They first
grew a special type of cell called dendritic cells (or monocytes), which stimulated the T
cells and 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. Investigators 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 in the laboratory). They also 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 were treated with radiation so they cannot grow. Once sufficient
numbers of T cells are made, investigators 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 they tested
the cells against the skin cells or against T cells that they 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. Investigators 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.
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 the Methodist Hospital.
FOLLOW-UP STUDIES We will follow the subject after the injections. Total time participation
for this study will be 15 years.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Safety and MTD of 2 IV injections of autologous/syngeneic or allogeneic TGFb resistant LMP2A-specific cytotoxic T-lymphocytes.
Helen E Heslop, MD
Baylor College of Medicine
United States: Food and Drug Administration
|The Methodist Hospital||Houston, Texas 77030|
|Texas Childrens Hospital||Houston, Texas 77030|