District of Columbia
PIDD represent an expanding group of genetic disorders that compromise immunity against
bacteria, viruses, and fungi. The most severe forms of PIDD cause profound susceptibility to
opportunistic infections due to impaired or absent T-cell immunity. These diseases can be
rapidly fatal unless treated via hematopoietic stem cell transplantation (HSCT). Chronic
viral illnesses are a common presenting feature of many of these disorders, and studies have
shown that survival of HSCT is profoundly impacted by the patient's pre-transplant disease
status. Primary infections with viruses such as cytomegalovirus (CMV) and Epstein-Barr virus
(EBV) are common, and respiratory viruses such as adenovirus also frequently cause infection.
In patients with severe combined immunodeficiency (SCID), a prior study identified these
viruses as the most common causes of mortality in the immediate period following HSCT. Though
some forms of PIDD are amenable to HSCT without requiring conditioning chemotherapy, many
forms require a variable degree of pre-conditioning to ensure that stable engraftment of the
donor cells is achieved. The administration of cytotoxic chemotherapy used in the
conditioning regimens can however increase the risk for regimen related toxicity and for some
patients (especially those with active viral infections) this risk is particularly high,
leading to high treatment related mortality rates. For these reasons, many such patients are
not even considered candidates for HSCT or are delayed getting to HSCT and ultimately succumb
to infection before they can receive the transplant.
The primary objective of this study is to determine the safety of administering third-party
multivirus-specific cytotoxic T lymphocytes (mCTL) from adult CMV seropositive donors to
treat refractory viral infections in patients with primary immunodeficiency disorders (PIDD)
prior to hematopoietic stem cell transplantation (HSCT).
Since recovery of virus-specific T cells is clearly associated with protection from infection
with each of these viruses, adoptive immunotherapy to decrease the time to immune
reconstitution is an attractive approach. Virus-specific T cells generated by repeated
stimulation with antigen presenting cells (APCs) expressing viral antigens have been
evaluated in clinical trials to prevent and treat viral infections in immunocompromised
hosts. This approach eliminates alloreactive T cells.
To broaden the specificity of single CTL lines to include the three most common viral
pathogens of stem cell recipients, investigators reactivated CMV and adenovirus-specific T
cells by using mononuclear cells transduced with a recombinant adenoviral vector encoding the
CMV antigen pp65 (Ad5f35CMVpp65). Subsequent stimulations with EBV-LCL transduced with the
same vector both reactivated EBV-specific T cells and maintained the expansion of the
activated adenovirus and CMV-specific T cells. This method reliably produced CTLs with
cytotoxic function specific for all three viruses, which investigators infused into 14 stem
cell recipients in a Phase I prophylaxis study. They observed recovery of immunity to CMV and
EBV in all patients but an increase in adenovirus-specific T cells was only seen in patients
who had evidence of adenovirus infection pre-infusion. A follow-up study in which the
frequency of adenovirus-specific T cells was increased in the infused CTLs produced similar
results, thus highlighting the importance of endogenous antigen to promote the expansion of
infused T cells in vivo. Nevertheless, all patients in both clinical trials with pre-infusion
CMV, adenovirus or EBV infection or reactivation were able to clear the infection, including
one patient with severe adenoviral pneumonia requiring ventilatory support. CTLs recognizing
multiple antigens can therefore produce clinically relevant effects against all three
1. Diagnosis of primary immunodeficiency with established plan to undergo myeloablative
or non-myeloablative allogeneic hematopoietic stem cell transplant for treatment
thereof or diagnosis of a form of primary immunodeficiency for which hematopoietic
stem cell transplantation is not indicated.
2. Active infection with EBV, CMV, and/or Adenovirus, unable to be successfully
controlled with standard therapy.
3. Steroids less than 0.5 mg/kg/day prednisone
4. Karnofsky/Lansky score of ≥ 50
5. ANC greater than 500/µL.
6. Bilirubin <2x, AST <3x, Serum creatinine <2x upper limit of normal, Hgb >8.0
7. Pulse oximetry of > 90% on room air
8. Negative pregnancy test (if female of childbearing potential)
9. Patient or parent/guardian capable of providing informed consent.
1. Patients with other uncontrolled infections (see 2.3.2 for definitions)
2. Patients who received ATG, Campath, or other T cell immunosuppressive monoclonal
antibodies in the last 28 days
3. Received donor lymphocyte infusion in last 28 days
4. Diagnosis of Omenn's syndrome or MHC class I deficiency
5. Active and uncontrolled malignancy
6. Pregnant or lactating
7. Unable to wean steroids to ≤0.5 mg/kg/day prednisone.
8. Patients with Grade 3 hyperbilirubinemia
Catherine Bollard, MD
Children's Research Institute
Fahmida Hoq, MBBS, MS
Washington, D.C., District of Columbia 20010
Fahmida Hoq, MBBS, MS
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