Therapeutic Effects Of Epstein-Barr Virus Immune T-Lymphocytes Derived From A Normal HLA- Compatible Or Partially- Matched Third-Party Donor in the Treatment of EBV Lymphoproliferative Disorders and EBV-Associated Malignancies

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Memorial Sloan-Kettering Cancer Center
Sponsor:
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT01498484
First received: December 21, 2011
Last updated: May 12, 2014
Last verified: May 2014
  Purpose

This study is testing to see how well transfusions of T-cells work in treating Epstein-Barr Virus (EBV). These T-cells are made from the blood of normal donors who are immune to EBV. A transfusion is the process by which blood from one person is transferred to the blood of another. In this case the investigators are transferring Tcells. T-cells are a type of white blood cell that helps protect the body from infection.

Researchers have already seen complete and lasting remissions of EBV in a small group of bone marrow transplant recipients by giving them T-cells from their transplant donors. The T-cells are immune to EBV. A remission means a person's disease has gotten better. Based on this, researchers have been running a larger trial to see whether EBV-immune T-cells can help patients who have EBV without causing bad reactions. So far, they have not seen any patients get bad reactions from infusions of EBV-immune T-cells. Some patients who get EBV may respond to EBV-immune T-cells from donors other than their transplant donors. These donors are called "third party donors". Researchers use third party donors when they cannot make EBV-immune T-cells from the original transplant donor or if the patient did not receive a transplant. If the patient consents to this trial, the EBV-immune T-cells made from a third party donor will be used to treat and possibly cure their EBV disease. The patient will get at least three weekly transfusions of these cells on this trial.


Condition Intervention Phase
Non-Hodgkin's Lymphoma
Epstein-Barr Virus
Biological: EBV-specific T-cells
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of The Therapeutic Effects Of Epstein-Barr Virus Immune T-Lymphocytes Derived From A Normal HLA- Compatible Or Partially- Matched Third-Party Donor in the Treatment of EBV Lymphoproliferative Disorders and EBV-Associated Malignancies

Resource links provided by NLM:


Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • efficacy [ Time Frame: 3 weeks ] [ Designated as safety issue: No ]
    The responses of the clinically and/or radiologically evident EBV LPD or malignancies will be identified three weeks post-infusion cycle as complete remission, partial remission, stable disease, or no response with disease progression based on the following criteria. Outcome responses will be captured post-first cycle and post final-cycle of infusions of EBV specific T cells. Best response observed in the full course of treatment will also be recorded as a distinct entity.


Secondary Outcome Measures:
  • remaining EBV-LPD free [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Complete remission: Complete resolution of all clinical and radiologic evidence of lymphoma, confirmed by biopsy of affected tissues when indicated, lasting for at least three weeks following completion of a course of cell infusions.


Estimated Enrollment: 56
Study Start Date: December 2011
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group 1

Group 1 will consist of:

A. Allogeneic marrow graft recipients who are severely immunocompromised and may have more prolonged or sustained T cell engraftment and, therefore, could be at risk for GvHD B. Patients with severe congenital or antineoplastic drug induced immunodeficiency who could be durably engrafted and are therefore at risk for GvHD

Biological: EBV-specific T-cells
Patients in Group 1 will each receive a course of three weekly infusions of EBV-specific T-cells. Each weekly dose will provide 2 x106 T-cells/Kg recipient weight (+/- 3 days) from the donor's EBV-specific T-cell line. After the third dose, patients will be observed for at least 3 weeks.
Experimental: Group 2

Group 2 will consist of:

A. Organ allograft recipients. Although immunocompromised, these patients can reject third party blood cells. Thus, the risk of sustained engraftment or GvHD is low B. AIDS patients who will almost invariably reject the infused T-cells and are therefore at very low risk of GvHD C. Patients who develop other EBV-associated malignancies without pre-existing immune deficiency who are also expected to reject the infused T cells and are at low or no risk of GvHD

Biological: EBV-specific T-cells
Patients in Group 2 will also receive 3 weekly intravenous infusions of 2 x 106 EBV-specific T-cells/kg recipient weight (+/- 3 days). After the third dose, patients will be observed for at least 3 weeks.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Pathologically documented EBV antigen positive lymphoproliferative disease, lymphoma or other EBVassociated malignancy.

OR

  • Evaluable disease as demonstrated by clinical and/or radiologic studies with elevated blood levels of EBVDNA exceeding 500 copies/μl by quantitative real time pcr.

OR

  • Persistent or recurrent elevations in levels of EBVDNA exceeding 500 copies/μl in patients previously treated for EBVLPD with chemotherapy and/or Rituxan who do not yet have clinically or radiologically evaluable disease but are at high risk of disease recurrence.
  • EBV-specific T-cells from donor of the patient's transplant are not available.
  • EBV-specific T-cells are available for adoptive immune cell therapy from a consenting third party donor. The third party EBV CTLs to be administered will be selected on the basis of two criteria: 1) that they are matched for at least 2 HLA antigens and 2) that they are restricted by an allele shared with the EBV+ malignancy (if known), or with the donor in HSCT recipients, or patient in organ transplant or immunodeficient patients
  • KPS or Lansky score ≥ 20.
  • A life expectancy of at least 6 weeks.
  • Adequate bone marrow, heart, lung, liver and kidney function at the time treatment with EBV-specific
  • T-cells is initiated, including:

    1. Absolute neutrophil count (ANC) ≥ 1K/mcL, with or without GCSF support
    2. Platelets ≥ 20,K/mcL
    3. Creatinine ≤ 2.0mg/dl
    4. ALT, AST < 3.0x and total bilirubin < 2.5x the institutional ULN
    5. Stable blood pressure and circulation not requiring pressor support
    6. Adequate cardiac function as demonstrated by EKG and/or echocardiographic evidence (may be performed within 30 days prior to treatment)
  • However, abnormalities of specific organs will not be considered grounds for exclusion if they are the result of the EBV+ malignancy or its treatment (e.g. a renal allograft recipient with an EBVLPD may be on dialysis because the allograft was rejected when the immune suppression was stopped as a first approach to treatment of the EBVLPD).
  • There is no age restriction to eligibility for this protocol.
  • It is expected that five types of patients afflicted with EBV-associated lymphomas, lymphoproliferative diseases or malignancies will be referred and will consent to participate in this trial. These are:
  • Patients developing EBV lymphomas or lymphoproliferative disorders following an allogeneic hematopoietic progenitor stem cell transplant (HSCT) (ie: marrow, PBSC, or umbilical cord blood). In these cases, the HSCT donor, if EBV-seropositive, will be used as the donor of EBV-specific T-cells for adoptive immunotherapy wherever possible, because the EBV-LPD are almost invariably derived from that marrow donor. These patients will be enrolled onto protocol # IRB 95-024. However, if the HSCT donor is EBV seronegative or not readily available (e.g. a cord blood transplant), the patient will be a candidate to receive EBV- specific T-cells generated from a third party seropositive donor that have been generated and stored in the MSKCC bank of cryopreserved immune T-cells for adoptive cell therapy. For these patients, the third party donor derived T cells to be used will be selected primarily on the basis of matching for 2 HLA alleles shared by the transplant donor and recipient. However, priority is given to T cells partially matched with, and restricted by, HLA alleles of the transplant donor, since EBV + lymphomas in HSCT recipients are usually (but not always) derived from the transplant donors' cells.
  • Patients developing EBV lymphomas or lymphoproliferative disorders following an allogeneic organ transplant. In these cases, the lymphoma is usually of recipient origin. EBV-specific T-cells will be selected from the MSKCC Bank expanded from an EBV-seropositive normal donor who is at least matched for 2 HLA alleles with the EBV lymphoma. If the origin of the lymphoma is unknown, T-cells partially matched with the transplant recipient will be used, since these lymphomas are usually of host origin. Using this approach to donor selection, it is expected that the EBV-specific, HLA restricted cytotoxic T-cells expanded from the HLA partially-matched donor would be able to recognize and kill lymphoma cells presenting EBV antigens in the context of an appropriate HLA restricting element. Priority will be given to the use of partially matched EBV specific T cells known to be restricted by an HLA allele shared by the lymphoma (or, if unknown, the patient).
  • Patients with AIDS developing EBV lymphomas or lymphoproliferative diseases as a consequence of the profound acquired immunodeficiency induced by HIV. For such patients, EBV specific T-cells from third party seropositive donors who are HLA compatible in at least 2 HLA alleles shared by the patient will be used.

Selection of T cells known to be restricted by an HLA allele shared by the patient will be given priority.

  • Patients who develop EBV lymphomas or lymphoproliferative diseases or other EBV-associated malignancy as a consequence of profound immunodeficiencies associated with a congenital immune deficit or acquired as a sequela of anti-neoplastic or immunosuppressive therapy. For these patients, normal, EBV specific T-cells from third party seropositive donors who are HLA compatible in at least 2 HLA alleles shared by the patient will be used. Again, selection of T cells known to be restricted by an HLA allele shared by the patient will be given priority.
  • Patients who develop other EBV-associated malignancies without pre-existing immune deficiency, including: EBV+ Hodgkin's and Non-Hodgkin's disease, EBV+ nasopharyngeal carcinoma, EBV+ hemophagocytic lymphohistiocytosis, or EBV+ leiomyosarcoma. Normal, EBV specific T-cells from third party seropositive donors who are HLA compatible in at least 2 HLA alleles shared by the patient will be used. Again, selection of T cells known to be restricted by an HLA allele shared by the patient will be given priority.

Donor Eligibility

  • Donors in Groups 1 and 2 (Section 5.1) would have already been determined to be eligible and will have donated blood or leukocytes to establish EBV-specific T-cells under IRB # 05-065, 07-055, 95-024 or 12-086. There are no additional eligibility requirements for these donors.
  • Donors in Group 3 (section 5.1), however, will need to meet the following eligibility requirements prior to donation:
  • Donors must satisfy the criteria specified in FDA 21 CFR 1271 Donors must be typed for HLA-A, B, C and DR
  • Donors must have a hemoglobin value > 10g/dl
  • Donors must be capable of undergoing, at least, a single standard 2 blood volume leukapheresis or a donation of one unit of whole blood

Exclusion Criteria:

Patient Exclusion Criteria

The following patients will be excluded from this study:

  • Patients with active (grade 2-4) acute graft vs. host disease (GVHD), chronic GVHD or an overt autoimmune disease (e.g. hemolytic anemia) requiring high doses of glucocorticosteroid (>0.5 mg/kg/day prednisone or its equivalent) as treatment
  • Patients who are pregnant
  • Patients with severe comorbidities, not related to their EBV-associated malignancy, that would be expected to preclude their survival for the 6 weeks required to assess response of T cell therapy Donor Exclusion Criteria
  • HTLV/HIV(+) or Hepatitis B or C antigen(+) donors
  • Donors who are known EBV seronegative
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01498484

Contacts
Contact: Richard O'Reilly, MD 212-639-5957
Contact: Ekaterina Doubrovina, MD, PhD 646-888-2746

Locations
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Richard O'Reilly, MD    212-639-5957      
Contact: Ekaterina Doubrovina, MD, PhD    646-888-2746      
Principal Investigator: Richard O'Reilly, MD         
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Investigators
Principal Investigator: Richard O'Reilly, MD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT01498484     History of Changes
Other Study ID Numbers: 11-130
Study First Received: December 21, 2011
Last Updated: May 12, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Memorial Sloan-Kettering Cancer Center:
EBV-specific T-cell lines
11-130

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoproliferative Disorders
Virus Diseases
Neoplasms by Histologic Type
Neoplasms
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases

ClinicalTrials.gov processed this record on July 20, 2014