Description:
Patients have a type of a lymph node cancer called lymphoma, a tumor of the nasal passages
called nasopharyngeal carcinoma (NPC), a tumor of a particular type of muscle called
leiomyosarcoma (LMS) or a condition called severe chronic active EBV (SCAEBV) syndrome. The
disease has come back, may come back or has not gone away after treatment. This voluntary
research study uses special immune system cells called LMP-specific cytotoxic T lymphocytes,
a new experimental therapy.
Some patients with these diseases show evidence of infection with the virus that causes
infectious mononucleosis (called Epstein-Barr virus, or EBV) before or at the time of their
diagnosis. EBV is found in the cancer cells of up to half of the patients with lymphomas, and
in some cases of NPC and LMS, suggesting that it may play a role in causing these diseases.
Those cancer cells (as well as some B cells in SCAEBV) that are 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 T cells, that have been trained to kill cells infected by EBV can survive
in the blood and affect the tumor.
This treatment with specially trained T cells has had activity against these viruses when the
cells are made from patients with those diseases (or, after bone marrow transplant, from the
patient's transplant donor). However, sometimes it is not possible to grow these cells; other
times, it may take 2 to 3 months to make the cells, which may be too long when one has an
active tumor. We are therefore asking if subjects would like to participate in this study,
which tests if blood cells from a donor that is a partial match with the subject (or the
transplant donor) that have been grown in the way described above can survive in the blood
and affect the disease.
These LMP-specific CTLs are an investigational product not approved by the Food and Drug
Administration.
Title
- Brief Title: Most Closely HLA-Matched CTLs for Relapsed Epstein Barr Virus(EBV)-Associated Diseases
- Official Title: Most Closely HLA-Matched Allogeneic LMP1/2-Specific Cytotoxic T Lymphocytes for Treatment of Patients With Relapsed EBV-Associated Diseases
Clinical Trial IDs
- ORG STUDY ID:
H-28361-MALTED
- SECONDARY ID:
MALTED
- NCT ID:
NCT01447056
Conditions
- Hodgkin Lymphoma
- Non-Hodgkin Lymphoma
- Lymphoproliferative Disorder
- Nasopharyngeal Carcinoma
- Leiomyosarcoma
- Severe Chronic Active EBV (SCAEBV)
Interventions
| Drug | Synonyms | Arms |
|---|
| LMP specific T cells | | LMP Specific T cells |
Purpose
Patients have a type of a lymph node cancer called lymphoma, a tumor of the nasal passages
called nasopharyngeal carcinoma (NPC), a tumor of a particular type of muscle called
leiomyosarcoma (LMS) or a condition called severe chronic active EBV (SCAEBV) syndrome. The
disease has come back, may come back or has not gone away after treatment. This voluntary
research study uses special immune system cells called LMP-specific cytotoxic T lymphocytes,
a new experimental therapy.
Some patients with these diseases show evidence of infection with the virus that causes
infectious mononucleosis (called Epstein-Barr virus, or EBV) before or at the time of their
diagnosis. EBV is found in the cancer cells of up to half of the patients with lymphomas, and
in some cases of NPC and LMS, suggesting that it may play a role in causing these diseases.
Those cancer cells (as well as some B cells in SCAEBV) that are 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 T cells, that have been trained to kill cells infected by EBV can survive
in the blood and affect the tumor.
This treatment with specially trained T cells has had activity against these viruses when the
cells are made from patients with those diseases (or, after bone marrow transplant, from the
patient's transplant donor). However, sometimes it is not possible to grow these cells; other
times, it may take 2 to 3 months to make the cells, which may be too long when one has an
active tumor. We are therefore asking if subjects would like to participate in this study,
which tests if blood cells from a donor that is a partial match with the subject (or the
transplant donor) that have been grown in the way described above can survive in the blood
and affect the disease.
These LMP-specific CTLs are an investigational product not approved by the Food and Drug
Administration.
Detailed Description
First, we will search our cell bank to see if there is a CTL line that is a match with the
subject and his/her donor. This matching is done using HLA type, which measures 6 proteins on
the cell surface. If HLA type has not been previously checked, we will do a blood draw (half
to one tablespoon) so that this can be done.
These CTL lines have been made at Baylor College of Medicine from donors for other transplant
patients or other normal donors from the National Marrow Donor Program. All donors have been
screened in the same way that we screen blood donors. When the CTL lines were made, blood was
taken from the donors and used to grow T cells. To do this, we first grew a special type of
cells called dendritic cells or monocytes and we put a specially produced human virus
(adenovirus) that carries the LMP genes into the dendritic cells or monocytes. They were then
used to stimulate T cells. This stimulation trained the T cells to kill cells with LMP on
their surface.
We then grew these LMP specific CTLs by more stimulation with EBV infected cells (made from
the same blood). We also put the adenovirus that carries the LMP genes into these EBV
infected cells so that we increased the amount of LMP that these cells had. These EBV
infected cells were treated with radiation so they could not grow. Once we made sufficient
numbers of T cells, we tested them to make sure they kill cells with LMP on their surface and
froze them.
To make sure that these cells won't attack the subject's tissues, we will also test the cells
against his/her own cells, which we will grow in the laboratory.
If the level of circulating T-cells in the patient is relatively high, s/he will receive one
treatment of cyclophosphamide. This drug will decrease the numbers of the patient's own
T-cells before the investigators infuse the LMP-specific cytotoxic T-lymphocytes. If the
patient is already receiving chemotherapy, this may not be needed.
The LMP specific CTLs will be thawed and injected IV over 1-10 minutes. Initially, one dose
of T-cells will be given. If after the first dose, there is a reduction in the size of the
patient's disease, they can receive up to five additional doses of the T-cells if they wish.
This is a dose escalation study, which means that the doses of cells will be increased as
more patients are treated, as long as the lower doses are determined to be safe.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| LMP Specific T cells | Experimental | LMP specific T cells will be given by intravenous injection over 1-10 minutes through either a peripheral or a central line and the IV flushed with saline. The volume of infusion will depend upon the concentration of the cells when frozen, the dose level, and the size of the patient. | |
Eligibility Criteria
INCLUSION CRITERIA:
SCREENING:
1. Any patient, regardless of age or sex, with one or more of the following EBV-positive
or associated disorders, regardless of the histological subtype: - Hodgkin lymphoma -
Non-Hodgkin lymphoma - Lymphoproliferative disorder - Nasopharyngeal carcinoma -
Leiomyosarcoma - Severe chronic active EBV infection syndrome (SCAEBV), defined as
high EBV viral load in plasma or PBMC (> 4000 genomes per ug PBMC DNA) and/or biopsy
tissue positive for EBV
2. Karnofsky/Lansky score 50% or more.
3. Informed consent explained to and signed by patient or parent/guardian able to give
informed consent and given a copy.
TREATMENT:
1. Any patient, regardless of age or sex, with one or more of the following EBV-positive
or associated disorders, regardless of the histological subtype: - Hodgkin lymphoma -
Non-Hodgkin lymphoma - Lymphoproliferative disorder - Nasopharyngeal carcinoma -
Leiomyosarcoma - Severe chronic active EBV infection syndrome (SCAEBV), defined as
high EBV viral load in plasma or PBMC (> 4000 genomes per ug PBMC DNA) and/or biopsy
tissue positive for EBV
2. The disease needs to be in one of the following stages: - At diagnosis or in first
relapse AND the patient is unable to receive conventional chemotherapy for his/her
condition. - In second or subsequent relapse. - With residual disease after
autologous, syngeneic or allogeneic HSCT.
3. Life expectancy 6 weeks or more.
4. Tumor tissue is positive for EBV.
5. Karnofsky/Lansky score 50% or more.
6. Bilirubin less than 3 times higher than the normal limits, AST less than 5 times
higher than the normal limits, Hgb greater than 8.0 g/dL and serum creatinine less
than 3 times higher than the normal limits.
7. Pulse oximetry of greater than 90% on room air.
8. If post allogeneic HSCT, patient must not have less than 50% donor chimerism in either
peripheral blood or bone marrow.
9. Clinical status at enrollment to allow tapering of steroids to less than 0.5 mg/kg/day
prednisone at time of treatment.
10. Informed consent explained to and signed by patient or parent/guardian able to give
informed consent and given a copy.
11. Sexually active patients must be willing to utilize one of the more effective birth
control methods during the study and for 3 months after the study is concluded. The
male partner should use a condom.
EXCLUSION CRITERIA:
SCREENING:
1. Known HIV positivity.
TREATMENT:
1. Currently receiving any investigational agents or have received any tumor vaccines
within previous 4 weeks.
2. Active acute grade III-IV graft-versus-host disease.
3. Severe intercurrent infection.
4. Received alemtuzumab or other anti-T-cell antibody within 28 days.
5. HIV seropositivity.
6. Pregnancy (due to unknown effects of this therapy on a fetus) or lactation.
7. Tumor in a location where enlargement could cause airway obstruction.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | N/A |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Patients with dose limiting toxicities after T-cell infusions |
| Time Frame: | 6 weeks |
| Safety Issue: | |
| Description: | To determine the safety of intravenous injections of third-party, partially HLA- matched, allogeneic Epstein Barr Virus (EBV)-specific cytotoxic T-lymphocytes (CTL) in patients with severe chronic active EBV (SCAEBV) infection or EBV-associated Hodgkin or non-Hodgkin lymphomas (HL/NHL), other lymphoproliferative disorders (LPD) or other malignancies (leiomyosarcoma and nasopharyngeal carcinoma) |
Secondary Outcome Measures
| Measure: | Safety and response to a repeated dosage regimen |
| Time Frame: | 5 years |
| Safety Issue: | |
| Description: | To obtain preliminary information on the safety and response to a repeated dosage regimen. |
| Measure: | Analysis of immune function of CTLs |
| Time Frame: | 5 years |
| Safety Issue: | |
| Description: | To determine the survival and the immune function of third-party allogeneic EBV-specific CTL lines |
| Measure: | Number of patients with an EBV and/or disease response to the CTLs |
| Time Frame: | 6 weeks |
| Safety Issue: | |
| Description: | To assess anti-EBV and anti-tumor effects of third-party partially HLA- matched allogeneic EBV-specific CTL lines. |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | Baylor College of Medicine |
Trial Keywords
- Hodgkin lymphoma
- Non-Hodgkin lymphoma
- Lymphoproliferative disorder
- Nasopharyngeal carcinoma
- Leiomyosarcoma
- EBV Cytotoxic T Lymphocytes
Last Updated
February 7, 2020
