• Survival of patients with SCID or PID undergoing this therapy. [ Time Frame: 1 Year ] [ Designated as safety issue: Yes ]
• To investigate whether the combination of anti-CD45, anti-CD52 and fludarabine followed by transplantation of CD34+ selected cells can be performed with minimal and acceptable short term toxicity. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
• To investigate the incidence of grade III - IV acute GVHD for patients with SCID following transplantation of CD34+ selected donor using MAb conditioning. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

This study is to discover whether children with severe combined immunodeficiency disease (SCID) or other primary immunodeficiency disorder (PID) for which no satisfactory treatment other than stem cell transplantation (SCT) exists can be safely and effectively transplanted from HLA mismatched (up to one haplotype) related donors or unrelated matched or mismatched (up to one antigen) donors, when leukocytolytic monoclonal antibodies and Fludarabine are the sole conditioning agents. Three monoclonal antibodies will be used in combination. Two of them, YTH 24 and YTH 54 are rat IgG1 antibodies directed against two contiguous epitopes on the CD45 (common leucocyte) antigen. They have been safely administered as part of the conditioning regimen for 12 patients receiving allografts (HLA matched and mismatched) at this center. They produce a transient depletion of >90% circulating leucocytes. The third MAb is Campath 1H, a humanized rat anti-CD52 MAb. Campath 1H, Alemtuzumab, has been licensed to treat B-CLL and more recently has been safely given at this and other centers as part of a sub-ablative conditioning regimen to patients with malignant disease. Because these MAb produce both profound immunosuppression and significant, though transient, myelodestruction we believe they may be useful as the sole conditioning regimen in patients with SCID, in whom the use of conventional chemotherapeutic agents for conditioning may produce or aggravate unacceptable and even lethal short term toxicity. We anticipate MAb mediated subablative conditioning will permit engraftment in a high percentage of these patients with little or no immediate or long term toxicity. Campath IH persists in vivo for several days after administration and so will be present over the transplant period to deplete donor T cells as partial GvHD prophylaxis. Additional GvHD prophylaxis may be provided by administration of FK506.

Donor Stem Cell Processing for Mismatched Donors:

Harvested peripheral blood stem cells will be enriched for CD34 cells using the CliniMACS CD34 Reagent system, according to CAGT SOPs .

Stem Cell Transplant Conditioning:

Campath-1H will be given as 3 daily intravenous infusions and will be followed by Anti-CD45 which will be given as four daily intravenous infusions that will be completed two days prior to stem cell infusion. Diphenydramine will be administered i.v. q4h during the period of the course of the Campath and Anti-CD45 infusions.

Day 8 Campath 1H as per CAGT SOP Fludarabine 30 mg/m2 7 Campath 1H as per CAGT SOP Fludarabine 30 mg/m2 6 Campath 1H as per CAGT SOP Fludarabine 30 mg/m2 5 YTH 24/54 400ug/kg over 6 hr Fludarabine 30 mg/m2

• 4 YTH 24/54 400ug/kg over 6 hr Fludarabine 30 mg/m2
• 3 YTH 24/54 400ug/kg over 6 hr
• 2 YTH 24/54 400ug/kg over 6 hr
• 1 rest
• 0 Stem Cell Infusion

Campath 1H Infusion Campath dose is weight based: for patients less than 15 kg administer Campath 3 mg; for patients >15 kg to 30 kg administer Campath 5 mg; for patients > 30 kg administer Campath 10 mg. Campath will be dosed and administered as per CAGT SOP.

Anti-CD45 Infusion Anti-CD45 infusion will be administered according to CAGT SOPs. Pre-infusion (2 hr before each infusion), at the end of the infusion and 24 hr and 48 hr after the final (4th) infusion 3 ml of heparinized blood will be drawn to evaluate for free Anti-CD45 levels in the plasma before the next infusion is commenced. This estimation will be used to determine whether treatment with irradiated leukocytes is required before the bone marrow is infused.

GVHD Prophylaxis GVHD prophylaxis will be achieved through positive selection for CD34 resulting in > 3 log T cell depletion. Previous reports have indicated that there is a low frequency of severe (Grade II/IV) GVHD after haploidentical transplants if recipients receive stem cell populations containing <5 x 10 CD3 positive T cells. We hope to achieve such levels with our CD34 enrichment protocol. However, pharmacologic prophylaxis will be added if the CD34 selected product contains more than 5 x 10 CD3+ve T cells/kg recipient weight. In addition, Campath 1H persists in the recipient circulation through the immediate transplant period and will contribute anti-GVHD activity, in vivo. Patients who develop acute or chronic GVHD will be managed according to CAGT SOPs.

Supportive Care Patients receive supportive care as per CAGT SOPs. These SOPs include prophylactic antiviral, antibacterial, and antifungal medications, transfusion of blood products, infusion of IVIG, treatment of acute GVHD, PCP prophylaxis, and TPN. Patients will be closely monitored for opportunistic infections and receive prophylactic antimicrobial therapy when indicated.

CAGT SOPs may be superseded by an investigational study for which the patient is eligible.

PATIENT EVALUATION:

Baseline Evaluation (Prior to Administration of Anti-CD45) CBC, differential

There will also be measurement of indices of cardiac, renal, hepatic and pulmonary function that will determine whether the patient meets the eligibility criteria of Section 5.0.

Evaluation Related to Anti-CD45:

Brief physical exam daily Daily weight; Daily urinalysis

Blood sample: (3 ml) to be collected 40 -48 hours after last CD45 infusion This blood will be sent to Cell and Gene Therapy for the flow cytometric detection of free anti-CD45 (55). This estimation will be used to determine whether treatment with irradiated leukocytes is required before the bone marrow is infused

Stored Serum Samples: Serum will be prepared from 3 mL of blood at 40 hours and stored at -20°C. The serum samples will be used at a later time by the investigators for the detection of human anti-rat antibodies (HARA) if needed.

General evaluations will be conducted as per standard of care for patients receiving a PBSCT or Bone Marrow Transplant.

• Drug: Campath -1H
• Drug: Fludarabine
• Biological: Anti-CD45
• Procedure: Stem cell infusion

Inclusion Criteria:

- Patients with a diagnosis of: Severe combined immunodeficiency disease

This includes patients whose SCID is characterized by gene specific mutations as well as patients with clinically severe combined immunodeficiency without a defined genetic cause in which the diagnosis will be determined by a combination of clinical course with lymphocyte quantification and function assays.

OR

Severe primary immunodeficiency disorder, including undefined T cell deficiency disorder, Wiskott-Aldrich syndrome, and other severe immunodeficiencies for which satisfactory conventional therapy does not exist.

• Availability of an HLA mismatched (up to one haplotype) family member or an HLA matched or mismatched (up to one antigen) unrelated donor.
• Creatinine < 2.5 x normal for age.
• Life expectancy greater than 6 weeks
• HIV Seronegative
• Negative pregnancy test for females of childbearing age and willing to use an effective means of birth control.

Exclusion Criteria:

• Patients with an HLA matched related donor
• Patients with symptomatic cardiac disease, or evidence of significant cardiac disease by echocardiogram (i.e., shortening fraction less than 25%
• Patients with known allergy to rat serum products
• Patients with a Lansky/Karnofsky performance index score less than 70%
• Patients with a severe infection that on evaluation by the Principal Investigator precludes ablative chemotherapy or successful transplantation