Allogeneic Stem Cell Transplantation for Advanced Neuroblastoma Using MHC Mismatched Related Donors

Allogeneic stem cell transplantation has been explored for patients with high risk neuroblastoma. Results have been mixed, with only small series and case reports. Recent reports, however, especially with haploidentical transplantation have been more encouraging. Eradication of neuroblastoma may be mediated by both components of the innate immune system (natural killer cells) and through the adaptive immune system via T-cell cytotoxicity and the development of a humoral response to tumor specific antigens and minor histocompatibility antigens. To overcome restrictions created by unavailability of Human leukocyte antigen (HLA) matched donors, stem cell grafts from haploidentical related donors have been explored. Historically, the use of full haplotype mismatched family member donors has been limited by the development of severe graft-versus-host disease and the high rate of graft failure. Graft failure can now be overcome by increasing immunosuppression and increasing the number of transplanted stem cells. The most effective means of graft versus host disease (GVHD) prophylaxis is T cell depletion of the donor marrow. A 3-4 log depletion will reduce the risk of developing significant GVHD to less than 10%. Methods to mobilize stem cells from the bone marrow into the peripheral blood and collect these stem cells by apheresis now increase the availability of stem cells by a magnitude. Selection devices have been developed that will prepare extremely pure populations of these CD34 cells with upwards of 5 logs depletion of contaminating T cells. The CliniMACS CD34 Reagent System is a medical device designed to select CD34+ hematopoietic cells from heterogeneous hematologic cell populations. The investigators intend to provide mismatched related hematopoietic stem cell transplantation to up to 10 patients with relapsed refractory neuroblastoma. Harnessing the potential for innate and adaptive immune responses through allogeneic Hematopoietic stem cell transplantation (HSCT) may provide cure for some patients with this tumor.


Eligibility Criteria:
Inclusion Criteria:

* Age 6 months - \<18 years
* Measurable tumor by routine imaging or bone marrow biopsy
* Patient must have an 3/6, 4/6, or 5/6 human leukocyte antigen (HLA)-mismatched related donor who is Epstein-Barr virus (EBV) seropositive
* Karnofsky score 60% or greater if 10yrs old or older, Lansky score 60% or greater if under 10yrs old
* Pulse ox \>90% on room air
* Recovered from toxic effects of prior chemotherapy
* Patient must not be pregnant
* Patient must be HIV negative
* Patient or responsible person must be able to understand and sign an informed consent
* Available donor without contraindication for stem cell collection

Exclusion Criteria:

* Pregnant and lactating women.
* Human immunodeficiency virus (HIV) positive patient.
* Uncontrolled intercurrent infection.
* Renal failure (Creatine \> 1.5 or Creatinine Clearance \< 40 ml/min/1.73m2)
* Active hepatitis or cirrhosis with liver test values greater than 3 times normal
* NOTE: Patients who would be excluded from the protocol strictly for laboratory abnormalities can be included at the investigator's discretion, after review by the Children's Mercy Hospital ethics board
* Donor Inclusion/Exclusion Criteria
* Donor must be in good health based on review of systems and results of physical examination, and routine testing per standards of good medical care.
* Female donors of childbearing age must have a negative pregnancy test and must not be lactating
* EBv seropositive
* Donor stem cells should be human leukocyte antigen (HLA) typed using molecular methods. See section 6.1.3 for HLA matching requirements.