Interleukin-2 Treatment for Wiskott-Aldrich Syndrome

Status:	Recruiting
Conditions:	Hematology
Therapuetic Areas:	Hematology
Healthy:	No
Age Range:	Any
Updated:	6/2/2016
Start Date:	October 2008
End Date:	October 2016
Contact:	Brenda Gwafila, RN
Email:	gwafilab@email.chop.edu
Phone:	267-426-9639

Reinstituting Natural Killer Cell Cytotoxicity and Cytoskeletal Dynamics in Wiskott-Aldrich Syndrome With IL-2 Therapy

Funding Source--FDA OOPD.

Orphan Product Grant Number--1R01FD004091-01A1

Context: Wiskott-Aldrich syndrome (WAS) is a fatal, devastating disease with ill-defined
treatment modalities, which affects young boys. Classic WAS is characterized by a clinical
triad of thrombocytopenia, eczema and severe, recurrent infections. Despite diagnostic and
therapeutic advances most WAS patients die at less than 12 years of age due to infections,
hemorrhage, malignancy or complications from treatments. WAS patients suffer from
herpesvirus infections as a result of poor Natural Killer (NK) cell function (cytotoxicity).
In the laboratory, the investigators have seen correction of WAS Natural Killer Cell (NK)
function after treatment with Interleukin-2 (IL-2).

Objectives: Initiate a prospective clinical trial by treating WAS subjects with IL-2 and
using safety as the primary endpoint. Restoration of NK cell cytotoxicity and effects on
cytoskeletal dynamics are secondary endpoints. The investigators will also observe patient
clinical status (eczema, infections, use of treatment dose antibiotics, food allergies,
etc).

Study Design/Setting/Participants: This is a prospective clinical trial treating 9 WAS
subjects in the Clinical Translational Research Center (CTRC) with IL-2.

Intervention: The investigators propose to subcutaneously administer 0.5 Million Units
(MU)/m2 of IL-2 daily to WAS subjects for 5 days. Research treatment will be repeated 2 and
4 months later. Inter-patient dose escalation will be employed to 1 MU/m2 and/or 2 MU/m2
based on safety as the primary endpoint.

Study Measures: The investigators will observe safety and tolerability measures and perform
assays on subject blood samples prior to and after research treatment to observe improvement
in NK cell function.

The Wiskott-Aldrich syndrome (WAS) is a fatal genetic disease of the immune system that
results from a mutation of the WAS protein (WASp) gene. Immune cells that carry this
mutation have a decreased ability to reorganize filamentous actin (F-actin) after
activation. As a result there are a number of defective immunologic functions, some of which
result in deficient host defense. The investigators have identified a pervasive deficit in
natural killer (NK) cell cytotoxicity in WAS patients. WAS patients suffer from conditions
that are hallmarks of NK cell deficiencies. These include severe herpesvirus infections and
B cell malignancies. Our lab and others have also found that exposure of WAS subject NK
cells to IL-2 in vitro restores NK cell function and allows for normal F-actin
reorganization. Thus, the investigators propose a proof of principal clinical trial to treat
WAS subjects with IL-2 to determine safety and efficacy of IL-2 in this population and if NK
cell function is restored ex vivo. If IL-2 can circumvent a defective WASp to restore NK
cell function, the investigators will propose a larger NIH funded efficacy trial of IL-2 in
WAS. The investigators will also use the in vivo treatment of WAS subjects to forward our
mechanistic studies of how IL-2 may facilitate F-actin reorganization in the absence of WASp
function.

Inclusion Criteria:

- Age: Subjects age greater than 24 months

- Weight: Subjects greater than 12.5 kilograms

- Disease status: WAS classified as Grade 1-4

- Informed Consent: Written informed consent of the subject (if an adult) or parental
permission, and assent of the child subject provided justification is made for the
inclusion of children in the study

Exclusion Criteria:

- Prior or planned hematopoetic transplant

- WAS classified as currently Grade 5 (Malignancy or autoimmune disease including the
following: Crohn's disease, scleroderma, thyroiditis, inflammatory arthritis,
diabetes mellitus, oculo-bulbar myasthenia gravis, crescentic IgA glomerulonephritis,
cholecystitis, cerebral vasculitis, Stevens-Johnson syndrome and bullous pemphigoid .
Not included here are: Hepatitis C virus induced vasculitis, alopecia areata and
systemic lupus erythematosus.)

- Known previous reaction to IL-2

- Subjects taking immunosuppressive medications that might alter study results

- Subjects taking nephrotoxic, cytotoxic, cardiotoxic, or hepatotoxic medications
(including medications for hypertension)

- Subjects currently taking systemic corticosteroids (not included here: topical and
inhaled corticosteroids)

- Subjects taking Interferon alpha

- Use of any other investigational agent in the last 30 days

- Women of childbearing potential not using contraception method(s), as well as women
who are breastfeeding

- Subjects with abnormal cardiac, hepatic and CNS function

We found this trial at

sites

Children's Hospital of Philadelphia

South 34th Street
Philadelphia, Pennsylvania 19104

215-590-1000