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Administration of Rapidly Generated Multivirus-specific Cytotoxic T-Lymphocytes for the Prophylaxis and Treatment of EBV, CMV, and Adenovirus Infection Post Allogeneic Stem Cell Transplant (VIRAGE)

Phase 1/Phase 2
Open (Enrolling)
Adenovirus Infection, Epstein-Barr Virus Infections, Cytomegalovirus Infections, Stem Cell Transplant

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Trial Information

Administration of Rapidly Generated Multivirus-specific Cytotoxic T-Lymphocytes for the Prophylaxis and Treatment of EBV, CMV, and Adenovirus Infection Post Allogeneic Stem Cell Transplant (VIRAGE)

Blood has been previously taken from the patient and the donor to make the cells.

To make the special cell line, special blood cells called dendritic cells (DCs)were made
first from the donor blood. Then, a specially produced gene called a plasmid that carries
the adenovirus, CMV, and EBV genes was introduced into the dendritic cells. Dendritic cells
with these new genes are then mixed with T cells to stimulate them. This stimulation trains
the donor T cells to kill cells that are infected with CMV, EBV, and adenovirus. Once a
sufficient numbers of T cells were made, they were tested to make sure they killed the
patient's cells infected with these viruses, but not the patient's normal cells, and were

If the donor has never been infected with CMV, the CTLs made for the patient may not have
activity against a CMV infection. If these donor CTLs show no activity against CMV
infection, the cells will not be given.

The patient may receive Benadryl (diphenhydramine) and Tylenol (acetaminophen). Then, the
donor's special cells will be thawed and injected into the patient's intravenous line. After
the patient receives the cells, the levels of these three viruses in the patient's blood
will be monitored. Investigators will also take blood to see how long the T cells given to
the patient are lasting in the patient's body.

If the special cell infusion has helped the infection or if the patient has had a treatment
(for example with steroid drugs) that might have destroyed the T cells that were given to
them, then the patient is allowed to receive up to 2 more doses of the cells.

The patient will continue to be followed by his/her transplant doctors after the injection.
The patient will either be seen in the clinic or contacted by a research nurse to follow up
for this study every week for 6 weeks then at 8 weeks, and 3, 6, and 12 months. The patient
may have other visits for standard care.

The patient will also have regular blood tests done to follow counts and the viral
infection. To learn more about the way the T cells are working in the patient's body, up to
an extra 30-40 ml (6-8 teaspoons) of blood will be taken before the infusion and then at 1,
2, 4, 6, and 8 weeks and 3 months. Blood should come from the central intravenous line, and
should not require extra needle sticks. Total time participation for this study will be 1

Inclusion Criteria


Patients will be eligible following any type of allogeneic transplant to receive CTLs as
prophylaxis or for early reactivations as defined below.

1. Prior myeloablative or non-myeloablative allogeneic hematopoietic stem cell
transplant using either bone marrow or peripheral blood stem cells.

2. Prophylaxis for patients at risk of CMV, adenovirus or EBV infection (for Phase 2
portion only). In the phase 1 portion patients must meet criteria in 3 below.

3. Early treatment of reactivation or infection which is defined for each virus as

1. CMV: CMV antigenemia is monitored at least weekly post transplant. Early
reactivation is defined at CMV antigenemia with less than 10 leucocytes
positive. If any patient develops CMV antigenemia (with greater than 10
leukocytes positive) or clinical evidence of CMV infection (defined as the
demonstration of CMV by biopsy specimen from visceral sites (by culture or
histology) either pre or after CTL infusions, standard treatment with
Ganciclovir, and/or Foscarnet and Immunoglobulins will be initiated. Patients
may receive CTLs for antigenemia or elevated PCR without visceral infection.

2. Adenovirus: Adenovirus infection will be defined as the presence of adenoviral
positivity as detected by PCR or culture from ONE site such as stool or blood or
urine or nasopharynx. Adenovirus disease will be defined as the presence of
adenoviral positivity as detected by culture from more than two sites such as
stool or blood or urine or nasopharynx. In patients who meet the criteria for
disease Cidofovir may be added unless the subject could not tolerate this agent
due to nephrotoxicity. Patients may receive CTLs for elevated PCR in blood or

3. EBV EBV-LPD is defined according to recent guidelines as proven EBV-LPD defined
by biopsy or probable EBV-LPD defined as an elevated EBV DNA level associated
with clinical symptoms (adenopathy or fever or masses on imaging) but without
biopsy confirmation. Patients with EBV DNA reactivation only defined as EBV DNA
levels > 1000 copies/ug may also receive CTLs on study. Patients with proven or
probable EBV-LPD should also receive Rituxan

4. Early treatment may be given to eligible patients with a single or multiple
infections. Patients with multiple infections with one reactivation and one
controlled infection are eligible to enroll.

5. Patient with a CMV seronegative donor may only receive CTLs for a CMV reactivation in
the dose escalation phase if the line has activity against CMV.

6. Clinical status at enrollment to allow tapering of steroids to less than 0.5
mg/kg/day prednisone.

7. Karnofsky/Lansky score of 50 or greater

8. ANC greater than 500/┬ÁL.

9. Bilirubin 2x upper limit normal or less

10. AST 3 x normal or less

11. Serum creatinine 2 x upper limit normal or less

12. HgB >8.0

13. Pulse oximetry of > 90% on room air

14. Available multi-virus-specific cytotoxic T lymphocytes

15. Negative pregnancy test in female patients if applicable (childbearing potential who
have received a reduced intensity conditioning regimen).

16. Written informed consent and/or signed assent line from patient, parent or guardian.

DONOR ELIGIBILITY: The donor for the CTL product will be the same donor who donated the
allogeneic product for the patient's transplant. These donors for allogeneic (i.e. HLA
matched or mismatched related or unrelated) stem cell transplants will have fulfilled
eligibility for and consented to stem cell donation as per the stem cell transplant
program's standard operating procedures.


Exclusion Criteria for initial CTL and for subsequent infusions:

1. Patients receiving ATG, or Campath or other immunosuppressive T cell monoclonal
antibodies within 28 days of screening for enrollment.

2. Patients with other uncontrolled infections. For bacterial infections, patients must
be receiving definitive therapy and have no signs of progressing infection for 72
hours prior to enrollment. For fungal infections patients must be receiving
definitive systemic anti-fungal therapy and have no signs of progressing infection
for 1 week prior to enrollment.

Progressing infection is defined as hemodynamic instability attributable to sepsis or
new symptoms, worsening physical signs or radiographic findings attributable to
infection. Persisting fever without other signs or symptoms will not be interpreted
as progressing infection.

3. Patients who have received donor lymphocyte infusion (DLI) within 28 days.

4. Patients with active acute GVHD grades II-IV.

5. Active and uncontrolled relapse of malignancy.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Assessment of dose limiting toxicity in subjects receiving rapidly-generated donor-derived multivirus-specific CTLs

Outcome Description:

Safety and toxicity outcomes including DLTs, GvHD, clinical signs of viral infections, secondary graft failure and laboratory measurements will be summarized using descriptive statistics for each dose level (frequency table, means, standard deviations, medians and ranges).

Outcome Time Frame:

42 days

Safety Issue:


Principal Investigator

Helen E Heslop, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Baylor College of Medicine


United States: Institutional Review Board

Study ID:




Start Date:

January 2011

Completion Date:

December 2015

Related Keywords:

  • Adenovirus Infection
  • Epstein-Barr Virus Infections
  • Cytomegalovirus Infections
  • Stem Cell Transplant
  • Epstein-Barr virus
  • CTL
  • cytotoxic T Lymphocytes
  • CMV
  • Adenovirus Infection
  • viral infection
  • hematopoietic stem cell transplantation
  • Adenoviridae Infections
  • Cytomegalovirus Infections
  • Virus Diseases
  • Epstein-Barr Virus Infections



Texas Children's Hospital Houston, Texas  
The Methodist Hospital Houston, Texas  77030