Alpha/Beta T and B Cell depletion with Zoledronic acid for solid tumors

Hematopoietic stem cell transplantation can cure patients with blood cancer and other underlying diseases. αβ-T cell and B cell depletion has been introduced to decrease GVHD and PTLD and has demonstrated effectiveness for hematologic malignancies and non-malignant diseases additionally increasing the donor pool as to allow for haploidentical transplant to safely occur.

While solid tumors can be highly chemotherapy sensitive, many remain resistant and require multimodalities of treatment. Immunotherapy has been developed to harness the immune system in fighting solid tumors, though not all have targeted effects. Some solid tumors are treated with autologous transplants; however, they do not always demonstrate an improved event free survival or overall survival. There has been evidence of the use of allogeneic stem cell transplants to provide a graft versus tumor effect, though studies remain limited.

By utilizing αβ-T cell and B cell depletion for stem cell transplants and combining with zoledronic acid, the immune system may potentially be harnessed and enhanced to provide an improved graft versus tumor effect in relapsed/refractory solid tumors and promote an improved event-free survival and overall survival.

This study will investigate the safety of treatment with a stem cell graft depleted of αβ-T cell and CD19+ B cells in combination with zoledronic acid in pediatric and young adult patients with select solid tumors, as well as whether this treatment improves survival rates in these patients.

Inclusion Criteria:

• Patients 6 months to ≤ 25 years old

• Relapsed/Refractory Solid Tumor whom failed or deemed ineligible to receive autologous transplant or if autologous transplant did not offer >20% chance of cure

With the following diseases:

1. neuroblastoma (high risk with relapsed or refractory disease),

2. relapsed/refractory rhabdomyosarcoma,

3. relapsed/refractory non-rhabdomyosarcoma soft tissue sarcoma (NRSTS): synovial sarcoma, malignant peripheral nerve sheath tumors (MPNST),

4. High risk adult type NRSTS: clear cell sarcoma, alveolar soft part sarcoma,

5. Other high-risk extracranial solid tumors: desmoplastic small round cell tumors, chordoma, malignant rhabdoid tumor, epithelioid sarcoma, myoepithelial tumor

6. relapsed/refractory bone tumors: osteosarcoma and Ewing sarcoma/PNET, or

7. other high-risk solid tumors with 16 years of age and Lansky scores for patients ≤16 years of age

• Adequate organ function (within 4 weeks of initiation of preparative regimen),

Defined as:

1. Pulmonary: FEV1, FVC, and corrected DLCO must all be ≥ 50% of predicted by pulmonary function tests (PFTs). For children who are unable to perform for PFTs due to age, the criteria are: no evidence of dyspnea at rest and no need for supplemental oxygen.

2. Renal: Creatinine clearance or radioisotope GFR ≥60 mL/min/1. 73 m2 or a serum creatinine based on age/gender

3. Cardiac: Ejection fraction of ≥ 40% by echocardiogram or radionuclide scan (MUGA).

• Written informed consent obtained from the subject and the subject agrees to comply with all the study-related procedures

• Individuals of childbearing potential (IOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for one year following transplantation to minimize the risk of pregnancy. Prior to study enrollment, individuals of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factor for an unintentional pregnancy.

• Subjects with female partners of child-bearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for one year following stem cell transplantation.

Exclusion Criteria:

• Patients with documented uncontrolled infection at the time of study entry are not eligible. a. Uncontrolled infection is patient without treatment antimicrobials and/or demonstrating progression despite antimicrobials

• Demonstrated lack of compliance with medical care, as determined by the treating physician.

• Patients who have received an allogeneic HSCT within 6 months.

• Patients who do not have an eligible allogeneic donor available.

• Patients with a life expectancy