The primary goal of this Phase I/II study is to assess the immune response and safety of
recombinant human CD40 ligand (rhuCD40L) in patients with X-linked hyper IgM syndrome
(XHIM). XHIM is a rare genetic disease caused by mutations in the gene encoding CD40
ligand. Individuals with this syndrome fail to make gamma immune globulin, frequently
suffer from opportunistic infections, and are at an increased risk of developing cancer.
Despite treatment with gamma globulin replacement therapy, the expected survival of patients
with XHIM is less than 20 percent by the age of 25.
In a mouse model of this syndrome, treatment with man-made CD40 ligand protein protected the
mouse from opportunistic infections, restored the mouse's ability to make gamma globulin,
and improved survival. We want to determine if a similar approach can work in humans with
XHIM. The study will be conducted at the Clinical Center of the National Institutes of
Health in Bethesda, Maryland.
For most patients, rhuCD40L will be administered by injection under the skin over a period
of six months and follow-up exams are required at 2-month intervals for an additional 6
months. During the study, patients will be maintained on intravenous gamma globulin,
antibiotics to protect against opportunistic infection, and, if needed, growth factors to
control neutropenia. The immune response to rhuCD40Lwill be measured by routine methods
such as measuring a patient's ability to synthesize gamma globulin when challenged with
immunizations to keyhole limpet hemocyanin (KLH) and Bacteriophage Phi-X 174 (Phi-X 174).
Our long-term goal is to define a therapeutic regimen that will provide effective
immunological reconstitution to patients with XHIM and improve their life expectancy.
The purpose of this Phase I/II study is to evaluate clinical response and safety following
administration of recombinant human CD40 ligand (rhuCD40L) in up to 5 patients with X-linked
hyper IgM syndrome (XHIM). XHIM is a rare genetic disease caused by mutations in the gene
encoding CD40 ligand (CD154) and is characterized by hypogammaglobulinemia, opportunistic
infections, and an increased risk of neoplastic disease. Despite treatment with intravenous
gamma globulin, the expected survival of patients with XHIM is less than 20% by the age of
25. The proposed protocol is a proof of principle study designed to determine if
administration of rhuCD40L can reverse the core immunologic defects of patients with XHIM.
To this end, we will immunize patients with neo antigens, specifically keyhole limpet
hemocyanin (KLH) and Bacteriophage Phi-X 174 (PhiX174) to evaluate antigen-specific B and T
cell responses. Clinical response and toxicity will be evaluated using routine
hematological and clinical evaluation, quantitation of KLH and PhiX174 specific IgG in
serum, measurement of proliferation and cytokine production to KLH simulation in vitro, and
FACS analysis to quantitate memory B and T cells. Our long-term goal is to define a
therapeutic regimen that will provide effective immunological reconstitution to patients
with XHIM and improve life expectancy.
All patients must have a diagnosis of X-linked hyper IgM syndrome confirmed either by
molecular analysis of the CD40L gene or by flow cytometry analysis demonstrating the
failure of CD40L expression on activated T cells, and/or clear X-linked inheritance (with
multiple affected males) in association with defective CD40L expression.
Age greater than or equal to 4 years
Patient and or parent (for children under the age of 18) must be able to understand and
sign informed consent.
Life expectancy of greater than 6 months.
Average ANC of greater than 250 cells/microL measured over 3 days during the week prior to
planned administration of rhuCD40L.
Serious ongoing opportunistic infection.
Use of immune-based therapies other than IVIG such as corticosteroids (doses of prednisone
greater than 0.4 mg/kg/d for more than 4 weeks within the 6 months prior to enrolling in
the study or any use of corticosteroids equivalent to greater than or equal to 5 mg of
prednisone at the time of enrollment) or other immunomodulating drugs within 6 months
prior to enrollment in the study.
Current use of other investigational drugs.
Chronic liver disease or any confounding medical illness that in the judgement of the
investigators would pose added risk for study participants (e.g. cancer, severe allergies,
chronic renal or pulmonary disease).
SGOT, SGPT greater than 2 times normal range; and creatinine greater than 2.0 times normal
ANC less than 250/microL; Platelets less than 50,000/microL; Hematocrit less than 25