BMT for Severe Combined Immunodeficiency Disease

Severe Combined Immunodeficiency Disease (SCID) represents a group of diseases with many different causes but, in general, results in children who have severe defects in the function of their lymphocytes. The UCSF Pediatric BMT Program is studying the use of bone marrow stem cell transplants for children with SCID. Currently, bone marrow stem cell transplantation is the only known treatment for children with SCID.

The goals of this protocol are the following:

• To determine the most optimal approach for transplantation in order to increase engraftment of TCD transplants and the incidence of B cell engraftment with minimal toxicity in SCID patients.
• To determine efficacy and safety of CD34 enriched T cell depleted parental peripheral blood hematopoietic stem cells (PBSC).

Children with SCID have defective lymphocytes

Lymphocytes are a type of white blood cell in the body which are crucial for fighting infections. They consist of two general types of cells, T cells and B cells. T cells are responsible for fighting all types of germs, but they may also cause rejection of donor bone marrow and/or reactions called Graft Versus Host Disease (GVHD). GVHD occurs when T cells from the donor attack certain tissues (e.g., skin, liver, intestines) of the recipient.

B cells are essential for making certain chemicals or proteins called antibodies that help protect against bacterial and viral infections. Antibodies can be purified from healthy, normal blood donors and administered to children with SCID in the form of gammaglobulin infusions or injections.

Another type of white cell in the blood is called a natural killer (NK) cell. The exact function of NK cells is unknown, although it is thought that they may be important in rejecting donor bone marrow following the bone marrow transplant. Some patients with SCID have low to absent function of their NK cells.

The final major type of white cell in the blood is the neutrophil, which is very important for fighting bacterial and fungal infections. In general, the majority of patients with SCID have normal numbers and functions of their neutrophils.

BMT is the only known treatment for children with SCID

Bone marrow contains young cells which manufacture the essential components found in the blood, including platelets, which help prevent bleeding, white cells, which protect against infection, and red cells, which carry oxygen to tissues in the body. Bone marrow from a donor can be transplanted into a recipient in order to restore these functions (engraftment) and, for children with SCID in particular, the function of their T cells and B cells. For the majority of children undergoing a BMT for diseases other than SCID, pretransplant preparation or conditioning with chemotherapy and sometimes radiation therapy is essential in order to obtain engraftment. For many children with SCID, donor marrow may engraft without any conditioning, although some (up to 50%) will require additional pretransplant conditioning to eliminate any residual immune function and allow engraftment of donor marrow. However, in a majority (75-80%) of children with SCID who have a successful BMT, donor B cells do not engraft, so that most who are cured of their T cell deficiency will still require gammaglobulin for the rest of their lives.

Peripheral blood stem cells for children with SCID

A second source of bone marrow stem cells is the blood that circulates throughout the body in arteries and veins. It is known that when normal people are treated with a type of chemical normally made in small amounts in the body called G-CSF (granulocyte colony stimulating factor), increased numbers of stem cells leave the marrow and enter the blood stream. These cells, referred to as recruited peripheral blood stem cells, or PBSC, can be collected along with other white cells by a process called leukapheresis, a standard procedure commonly used in blood banks. In the past 10 years, leukapheresis has been used routinely for collecting stem cells from patients with cancer for subsequent transplantation back into the patient. Recently, it has been used for collecting stem cells from healthy parents or siblings for transplantation into matched or mismatched children or adult patients.

The UCSF Pediatric BMT Program is researching answers to the following questions regarding PBSC transplants:

1. How often will the transplants engraft?
2. How safe is the procedure?
3. Will there be a sufficient number of healthy donor stem cells to restore marrow function?
4. Will secondary or "booster" transplants be necessary after the initial transplant to accelerate the recovery of the immune system?
5. Are there any complications associated with this particular source of bone marrow stem cell?

Minimizing the risk of Graft Versus Host Disease

A major problem for patients who might benefit from a transplant is finding a compatible (tissue matched) donor, which reduces the risk of GVHD. Generally, 80% of children with SCID will have no closely matched donor available. Parents and many siblings are only partially compatible with their children and can only donate marrow or blood stem cells if it is treated to remove the T cells that are responsible for GVHD. Techniques are now available for purifying stem cells and removing T cells from mismatched marrow or peripheral blood from a mother, father or sibling which will allow it to be used safely when a closely matched relative is not available. One technique that is being used to select for stem cells and remove T cells utilizes the Baxter Isolex System. This involves targeting the stem cells with a monoclonal antibody attached to special iron chemical. When placed in a powerful magnetic field, the antibody-bound stem cells are collected. Over 1000 transplants have been done using the Isolex System to enrich for stem cells. Based on these results it appears that sufficient T cells can be removed to significantly reduce the risk of GVHD.

The UCSF Pediatric BMT Program is trying to determine 1) the most optimal regimen for treating a child with SCID that will result in both T and B cell engraftment, and 2) the safety and benefit of using stem-cell enriched, T-cell depleted PBSC from parents or siblings.

Eligibility

Patients who are eligible for this protocol have one of the following diagnoses:

• T-B-SCID
• T-B+SCID
• ADA deficiency
• Omenns
• PNP deficiency
• CD40 ligand deficiency
• Bare lymphocyte syndrome
• Zap70 deficiency
• SCID with small bowel atresia
• SCID with T and B cells but no function (PHA/MLR 10% of lower limit of normal).
• Reticular dysgenesis