Cytotoxic T-Lymphocytes for EBV-positive Lymphoma, GRALE
| Status: | Recruiting |
|---|---|
| Conditions: | Lymphoma, Hematology |
| Therapuetic Areas: | Hematology, Oncology |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 3/21/2019 |
| Start Date: | January 2013 |
| End Date: | July 2022 |
| Contact: | Helen E Heslop, MD |
| Email: | hheslop@bcm.edu |
| Phone: | 832-824-4662 |
Administration of Rapidly Generated LMP, BARF1 And EBNA1 Specific Cytotoxic T-Lymphocytes To Patients With EBV-Positive Lymphoma
Subjects have a type of lymph gland disease called Hodgkin or non-Hodgkin Lymphoma or
T/NK-lymphoproliferative disease or severe chronic active Epstein Barr Virus (CAEBV) which
has come back, is at risk of coming back, or has not gone away after treatment, including the
best treatment we know for these diseases.
Some patients with Lymphoma or T/NK-lymphoproliferative disease or CAEBV show signs of virus
that is called Epstein Barr virus (EBV) that causes mononucleosis or glandular fever ("mono"
or the "kissing disease") before or at the time of their diagnosis. EBV is found in the
cancer cells of up to half the patients with HD and NHL, suggesting that it may play a role
in causing Lymphoma. The cancer cells (in lymphoma) and some immune system cells (in CAEBV)
infected by EBV are able to hide from the body's immune system and escape destruction. We
want to see if special white blood cells, called GRALE T cells, that have been trained to
kill EBV infected cells can survive in the blood and affect the tumor.
We 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. We 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, T/NK-lymphoproliferative disease, and CAEBV, the tumor
cells and B cells only express 4 EBV proteins. In a previous study, we made T cells that
recognized all 9 proteins and gave them to patients with HD. Some patients had a partial
response to this therapy but no patients had a complete response. We then did follow up
studies where we made T cells that recognized the 2 EBV proteins seen in patients with
lymphoma, T/NK-lymphoproliferative disease and CAEBV. Those proteins are called LMP-1 and
LMP-2. The cells are called LMP-specific cytotoxic T-Lymphocytes (CTLs). We have treated over
45 people on those studies. About 63% of those patients who had disease at the time they got
the cells had responses including some patients with complete responses. This study will
expand on those results and we will try and make the T cells in the lab in a simpler faster
way. We will also make T cells that will still see the LMP proteins but also 2 other EBV
proteins called EBNA-1 and BARF. These cells are called GRALE T cells. These GRALE CTLs 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 GRALE T
cells created using this new manufacturing technique. We will learn what the side effects are
and to see whether this therapy might help patients with HD or NHL or EBV associated
T/NK-lymphoproliferative disease or CAEBV.
T/NK-lymphoproliferative disease or severe chronic active Epstein Barr Virus (CAEBV) which
has come back, is at risk of coming back, or has not gone away after treatment, including the
best treatment we know for these diseases.
Some patients with Lymphoma or T/NK-lymphoproliferative disease or CAEBV show signs of virus
that is called Epstein Barr virus (EBV) that causes mononucleosis or glandular fever ("mono"
or the "kissing disease") before or at the time of their diagnosis. EBV is found in the
cancer cells of up to half the patients with HD and NHL, suggesting that it may play a role
in causing Lymphoma. The cancer cells (in lymphoma) and some immune system cells (in CAEBV)
infected by EBV are able to hide from the body's immune system and escape destruction. We
want to see if special white blood cells, called GRALE T cells, that have been trained to
kill EBV infected cells can survive in the blood and affect the tumor.
We 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. We 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, T/NK-lymphoproliferative disease, and CAEBV, the tumor
cells and B cells only express 4 EBV proteins. In a previous study, we made T cells that
recognized all 9 proteins and gave them to patients with HD. Some patients had a partial
response to this therapy but no patients had a complete response. We then did follow up
studies where we made T cells that recognized the 2 EBV proteins seen in patients with
lymphoma, T/NK-lymphoproliferative disease and CAEBV. Those proteins are called LMP-1 and
LMP-2. The cells are called LMP-specific cytotoxic T-Lymphocytes (CTLs). We have treated over
45 people on those studies. About 63% of those patients who had disease at the time they got
the cells had responses including some patients with complete responses. This study will
expand on those results and we will try and make the T cells in the lab in a simpler faster
way. We will also make T cells that will still see the LMP proteins but also 2 other EBV
proteins called EBNA-1 and BARF. These cells are called GRALE T cells. These GRALE CTLs 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 GRALE T
cells created using this new manufacturing technique. We will learn what the side effects are
and to see whether this therapy might help patients with HD or NHL or EBV associated
T/NK-lymphoproliferative disease or CAEBV.
Subjects (or their syngeneic donor) will give blood for investigators to make
LMP/BARF1/EBNA-1 (GRALE) CTLs in the lab. These cells will be grown and frozen for the
subject.
Patients will be started on the lowest dose (1 of 3 different levels) of GRALE T cells. Once
that dose schedule proves safe, the next group of patients will be started at a higher dose.
This process will continue until all 3 dose levels are studied. If the side effects are too
severe, the dose will be lowered or the GRALE T cell injections will be stopped.
The GRALE T cells will then be thawed and injected into the subject over 2-10 minutes.
Initially, two doses of GRALE T cells will be given 2 weeks apart.
If after the 2nd infusion there is a reduction in the size of the lymphoma on CT or MRI scan
as assessed by a radiologist, the subject can receive additional doses of the GRALE T cells
if they wish (up to 6 times). Follow up testing will be collected just like after the 1st
infusion.
All of the treatments will be given by the Center for Cell and Gene Therapy at Texas
Children's Hospital or Houston Methodist Hospital.
We will follow the subjects after the injections. They will either be seen in the clinic or
the subject will be contacted by a research nurse yearly for 5 years.
If they receive additional doses of the GRALE T cells as described above, they will be
followed until 5 years after the last dose of GRALE T-cells.
LMP/BARF1/EBNA-1 (GRALE) CTLs in the lab. These cells will be grown and frozen for the
subject.
Patients will be started on the lowest dose (1 of 3 different levels) of GRALE T cells. Once
that dose schedule proves safe, the next group of patients will be started at a higher dose.
This process will continue until all 3 dose levels are studied. If the side effects are too
severe, the dose will be lowered or the GRALE T cell injections will be stopped.
The GRALE T cells will then be thawed and injected into the subject over 2-10 minutes.
Initially, two doses of GRALE T cells will be given 2 weeks apart.
If after the 2nd infusion there is a reduction in the size of the lymphoma on CT or MRI scan
as assessed by a radiologist, the subject can receive additional doses of the GRALE T cells
if they wish (up to 6 times). Follow up testing will be collected just like after the 1st
infusion.
All of the treatments will be given by the Center for Cell and Gene Therapy at Texas
Children's Hospital or Houston Methodist Hospital.
We will follow the subjects after the injections. They will either be seen in the clinic or
the subject will be contacted by a research nurse yearly for 5 years.
If they receive additional doses of the GRALE T cells as described above, they will be
followed until 5 years after the last dose of GRALE T-cells.
Inclusion Criteria at time of Procurement
1. Any patient, regardless of age or sex, with EBV-positive Hodgkin's or non-Hodgkin's
Lymphoma, (regardless of the histological subtype) or EBV
(associated)-T/NK-lymphoproliferative disease or Severe Chronic Active EBV (CAEBV) who
may subsequently be eligible for the treatment component
2. EBV positive tumor (can be pending at this time)
3. Weighs at least 12kg
4. Informed consent explained to, understood by and signed by patient/guardian.
Patient/guardian given copy of informed consent.
Inclusion Criteria at time of Infusion
1. Any patient, regardless of age or sex, with EBV-positive Hodgkin's or non-Hodgkin's
Lymphoma (regardless of histologic subtype), or EBV
(associated)-T/NK-lymphoproliferative disease or Severe Chronic Active EBV (CAEBV) and
In second or subsequent relapse (or first relapse or with active disease if
immunosuppressive chemotherapy contraindicated or multiply relapsed patients in
remission who have a high risk of relapse) OR any patient 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 Richter's transformation of CLL. (Group A)
OR
In remission or with minimal residual disease status after autologous or syngeneic
SCT. (Group B)
2. EBV positive tumor
3. Patients with life expectancy greater than or equal 6 weeks.
4. Patients with bilirubin less than or equal to 3x upper limit of normal, AST less than
or equal 5x upper limit of normal, and Hgb greater than or equal to 7.0 (may be a
transfused value).
5. Patients with a creatinine less than or equal to 2x upper limit of normal for age
6. Pulse oximetry of > 90% on room air
7. Patients should have been off other investigational therapy for 4 weeks prior to entry
in this study.
8. Patients with a Karnofsky/Lansky score of greater than or equal to 50
9. Sexually active patients must be willing to utilize one of the more effective birth
control methods during the study and for 6 months after the study is concluded. The
male partner should use a condom.
10. Informed consent explained to, understood and signed by patient/guardian.
Patient/guardian given copy of informed consent.
- CAEBV 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
- Patients with relapsed or refractory lymphoma that are eligible for a stem
cell transplant will not be treated on this study as an alternative to
transplant.
Exclusion Criteria at Time of Procurement
1. Active infection with HIV, HTLV, HBV, HCV (can be pending at this time)
Exclusion Criteria at Time of Infusion
1. Pregnant or lactating
2. Severe intercurrent infection.
3. Current use of systemic corticosteroids > 0.5 mg/kg/day
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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