Specific Cytotoxic T-Lymphocytes, EBV-positive Lymphoma, GRALE
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Purpose
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. We are asking subjects to volunteer to be in a research study using special immune system cells called LMP- specific cytotoxic T lymphocytes, a new experimental therapy.
Some patients with Lymphoma or T/NK-lymphoproliferative disease or CAEBV show signs of virus called that is sometimes 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 Hodgkin's and non-Hodgkin Lymphoma, 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 laboratory that recognized all 9 proteins and were able to successfully prevent and treat post transplant lymphoma. However, in Hodgkin disease and non-Hodgkin Lymphoma, 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 Hodgkin disease. 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 laboratory in a simpler faster way. We will also make T cells that will still see the LMP proteins but also two 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 Food and Drug Administration.
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 Hodgkin disease or non-Hodgkin Lymphoma or EBV associated T/NK-lymphoproliferative disease or CAEBV.
| Condition | Intervention | Phase |
|---|---|---|
|
Hodgkin's Disease Non-Hodgkin's Lymphoma Lymphoproliferative Disease Lymphoma |
Biological: LMP, BARF1 & EBNA1 specific CTLs: A Biological: LMP, BARF1 & EBNA1 specific CTLs : B |
Phase 1 |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Administration of Rapidly Generated LMP, BARF1 And EBNA1 Specific Cytotoxic T-Lymphocytes To Patients With EBV-Positive Lymphoma |
- Assessment of toxicity of escalating doses of LMP, BARF1 and EBNA1 CTLs [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]To determine the safety of escalating doses of 2 intravenous injections of autologous rapid LMP, BARF1 and EBNA1 specific cytotoxic T-lymphocytes (CTL) in patients with EBV-associated Hodgkin's Disease or non-Hodgkin's lymphoma or T/NK-lymphoproliferative disease and CAEBV.
- Determine survival and immune function of LMP/BARF1/EBNA1-specific cytotoxic T-lymphocyte lines [ Time Frame: 1 year ] [ Designated as safety issue: No ]To determine the survival and the immune function of LMP/BARF1/EBNA1-specific cytotoxic T-lymphocyte lines
- Assess anti-viral and anti-tumor effects of LMP/BARF1/EBNA1-specific CTL [ Time Frame: 1 year ] [ Designated as safety issue: No ]To assess the anti-viral and anti-tumor effects of LMP/BARF1/EBNA1--specific CTL
- Obtain preliminary information on safety and response to extended dosage regimen [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]To obtain preliminary information on the safety and response to an extended dosage regimen.
| Estimated Enrollment: | 28 |
| Study Start Date: | January 2013 |
| Estimated Study Completion Date: | December 2020 |
| Estimated Primary Completion Date: | December 2015 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: LMP, BARF1 & EBNA1 specific CTLs: A
Group A: Patients in second or subsequent relapse (or first relapse or with active disease if immunosuppressive chemotherapy contraindicated or multiple relapsed patients in remission who are at a high risk of relapse) or any patient with primary disease or in first remission if immunosuppressive chemotherapy is contraindicated. Each group will have the dose escalation done separately. Two patients will be entered at the starting dose level. Each patient will receive 2 injections, 14 days apart, according to the dosing schedules. If there are no dose limiting toxicities, the escalation will continue at the pre-specified dose levels. |
Biological: LMP, BARF1 & EBNA1 specific CTLs: A
Dose Level 1: 2 x 10^7 cells/ m2; 2 x 10^7 cells/m2 Dose Level 2: 2 x 10^7 cells/m2; 1 x 10^8 cells/m2 Dose Level 3: 1 x 10^8 cells/m2; 2 x 10^8 cells/m2 Other Name: LMP, BARF1 and EBNA1 specific CTLs
|
|
Experimental: LMP, BARF1 & EBNA1 specific CTLs : B
Group B: Patients in remission or with minimal residual disease (MRD) status after autologous or syngeneic SCT. Each group will have the dose escalation done separately. Two patients will be entered at the starting dose level. Each patient will receive 2 injections, 14 days apart, according to the dosing schedules. If there are no dose limiting toxicities, the escalation will continue at the pre-specified dose levels. |
Biological: LMP, BARF1 & EBNA1 specific CTLs : B
Dose Level 1: 2 x 10^7 cells/ m2; 2 x 10^7 cells/m2 Dose Level 2: 2 x 10^7 cells/m2; 1 x 10^8 cells/m2 Dose Level 3: 1 x 10^8 cells/m2; 2 x 10^8 cells/m2 |
Detailed Description:
Earlier subjects gave blood for us to make LMP/BARF1/EBNA-1 (GRALE) CTLs in the lab. These cells were grown and frozen for the subject.
The GRALE T cells will then be thawed and injected into the subject over 2-10 minutes. The subject may be pretreated with Tylenol and Benadryl. These are given to prevent a possible allergic reaction to the GRALE T cell administration. Initially, two doses of GRALE T cells will be given 2 weeks apart.
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.
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 as it had from the 1st infusion. CT scans, MRI, or nuclear imaging will be collected 1-3 months after the final infusion.
All of the treatments will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital or the 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. 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 at 2,4 and 6 weeks and 3,6,9 and 12 months after each infusion (8 times). The blood may be drawn from the central line at the time of the regular blood tests. We will use this blood to see how long the GRALE T cells last and to look at the immune response to the subjects cancer.
One additional blood sample might be drawn 3 to 4 days after the infusion. Please let the doctor know if it will be difficult to come in for this blood draw on Day 3 to 4.
Subjects will be on study for approximately 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.
Eligibility| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria at time of Procurement
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)
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 stem cell transplantation (SCT). (Group B)
- EBV positive tumor
- Weighs at least 12kg
- Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent.
Inclusion Criteria at time of Infusion
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)
- EBV positive tumor (can be pending at this time)
- Patients with life expectancy > 6 weeks.
- Patients with bilirubin < 3x upper limit of normal, AST < 5x upper limit of normal, and Hgb > 8.0 (may be a transfused value).
- Patients with a creatinine < 2x upper limit of normal for age
- Pulse oximetry of > 90% on room air
- Patients should have been off other investigational therapy for 4 weeks prior to entry in this study.
- Patients with a Karnofsky/Lansky score of > 50
- 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.
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
Exclusion Criteria at Time of Procurement
- Active infection with HIV, HTLV, HBV, HCV (can be pending at this time)
Exclusion Criteria at Time of Infusion
- Pregnant or lactating
- Severe intercurrent infection.
- Current use of systemic corticosteroids > 0.5 mg/kg/day
Contacts and Locations| Contact: Helen E Heslop, MD | 832-824-4662 | hheslop@bcm.edu |
| Contact: Vicky Torrano | 832-824-7821 | vxtorran@txch.org |
| United States, Texas | |
| Texas Children's Hospital | Recruiting |
| Houston, Texas, United States, 77030 | |
| Contact: Helen E Heslop, MD 832-824-4662 hheslop@bcm.edu | |
| Contact: Vicky Torrano 832-824-7821 vxtorran@txch.org | |
| The Methodist Hospital | Recruiting |
| Houston, Texas, United States, 77030 | |
| Contact: Helen E Heslop, MD 832-824-4662 hheslop@bcm.edu | |
| Contact: Vicky Torrano 832-824-7821 vxtorran@txch.org | |
| Principal Investigator: | Helen E Heslop, MD | BCM |
| Principal Investigator: | Cliona Rooney, PhD | BCM |
More Information
No publications provided
| Responsible Party: | Helen Heslop, Professor, Pediatric Hematology/Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine |
| ClinicalTrials.gov Identifier: | NCT01555892 History of Changes |
| Other Study ID Numbers: | H-29617-GRALE, GRALE |
| Study First Received: | March 13, 2012 |
| Last Updated: | January 26, 2013 |
| Health Authority: | United States: Food and Drug Administration United States: Institutional Review Board |
Keywords provided by Baylor College of Medicine:
|
EBV Hodgkin's Lymphoma Non-Hodgkin's Lymphoma Lymphoma Relapse Autologous or Syngeneic Stem Cell Transplant |
T/NK-lymphoproliferative disease LMP BARF1 EBNA1 |
Additional relevant MeSH terms:
|
Hodgkin Disease Lymphoma Lymphoma, Non-Hodgkin Lymphoproliferative Disorders Neoplasms by Histologic Type |
Neoplasms Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases |
ClinicalTrials.gov processed this record on May 16, 2013