Title
Treatment of Relapsed or Refractory Neuroblastoma and Osteosarcoma With Expanded Haploidentical NK Cells and Hu14.18-IL2
Treatment of Relapsed or Refractory Neuroblastoma and Osteosarcoma With Ex-Vivo Expanded and Activated Haploidentical NK Cells and Hu14.18-IL2
Phase
Phase 1Study Type
InterventionalStatus
WithdrawnIndication/Condition
Relapsed Neuroblastoma Recurrent Neuroblastoma Osteosarcoma ...Intervention/Treatment
Ex vivo Expanded and Activated Haploidentical Donor NK Cells Hu14.18-IL2Study Participants
0Subjects with relapsed or refractory neuroblastoma and osteosarcoma will receive ex-vivo expanded and activated natural killer (NK) cells from a haploidentical donor in conjunction with the immunocytokine, hu14.18-IL2.
Natural Killer cells, a type of white blood cell, circulate around the body and kill abnormal cells (cells that are malignant, damaged or infected with virus). Sometimes cancer cells adapt to the body's own NK cells and are able to avoid being killed by them. This clinical trial uses two strategies to overcome the cancer cells' ability to avoid NK cell-mediated death.
The first strategy involves giving NK cells from another individual to the patient (in other words, donor- or haploidentical-NK cells). This is done because NK cells from an individual who is haploidentical (half-matched genetic make-up) are still able to effectively kill the cancer cells. Unfortunately, only a limited number of NK cells can be obtained from a donor. So, to increase the number of cancer-killing NK cells that will be given to the patient, the donor NK cells will first be grown in a sterile laboratory environment and allowed to multiply many-fold before they are infused into the patient. This growing process also activates the donor NK cells, which increases their ability to kill cancer cells.
The second strategy to overcome the cancer cells' ability to avoid NK cell-mediated death is to administer the immunocytokine, hu14.18-IL2, every day for seven days after infusion of the donor NK cells. The antibody portion (hu14.18) of the immunocytokine molecule "flags" the neuroblastoma cells for destruction by NK cells and the cytokine portion (IL2) further activates the NK cells (as well as other anti-tumor immune effector cells).
Since the donor NK cells are from a haploidentical individual, they are different enough to be recognized as foreign cells and will be killed immediately ("rejected") by the patients own immune system unless the immune system is restrained. So, to allow the donor NK cells time to kill neuroblastoma cells before they are "rejected", a chemotherapy regimen is first given to the patient to temporarily restrain the patient's own immune system. This also allows "room" for the donor NK cells to live, multiply and function.
Four courses of treatment are planned for each subject. Each course of treatment will be approximately one month long and involves a week of chemotherapy followed by infusion of donor NK cells. Beginning the day after the donor NK cell infusion, hu14.18-IL2 is infused over four hours for seven consecutive days.
Haploidentical donor NK cells that are expanded and activated under current GMP conditions using K562-mbIL15-41BBL.
The immunocytokine, hu14.18-IL2, is a fusion protein comprised of one molecule of the anti-GD2 humanized monoclonal antibody, hu14.18, fused to two molecules of the cytokine, interleukin-2.
All subjects will receive Ex vivo Expanded and Activated Haploidentical Donor NK Cells + hu14.18-IL2
Inclusion Criteria: Relapsed or refractory neuroblastoma Relapsed or refractory Osteosarcoma Karnofsky/Lansky performance score > 50 Life expectancy ≥ 4 months Creatinine clearance or radioisotope GFR ≥ 60 ml/min/1.73m2 OR serum creatinine within normal limits based on age and gender ANC ≥ 750/µL Platelet count ≥ 50,000/µL Hemoglobin ≥ 8 g/dL Total bilirubin ≤ 1.5 x upper limit of normal for age ALT (SCPT) ≤ 5 x upper limit of normal for age Shortening fraction of ≥ 27% by echocardiogram OR Ejection fraction of ≥55% by MUGA No evidence of dyspnea at rest Pulse oximetry > 94% on room air If PFTs performed, FEV1/FVC must be > 60% All Osteosarcoma patients must have PFTs performed CNS toxicity ≤ Grade 2 Patients with seizure disorders may be enrolled if seizures are well controlled on anticonvulsant therapy > 100 days after autologous stem cell infusion following myeloablative therapy ≥ 2 weeks since chemotherapy ≥ 7 days since anti-neoplastic, non-myelosuppressive biologic agent (or extended for agents known to have adverse events beyond the 7- day period) ≥ 2 weeks for local palliative XRT ≥ 6 months if prior craniospinal axis XRT (> 50%) ≥ 6 months if > 50% radiation of pelvis ≥ 6 weeks after therapeutic 131I-MIBG ≥ 6 weeks since thoracotomy Informed consent obtained (patient or legal representative) Women of reproductive potential must have negative pregnancy test and be willing to use effective birth control method Suitable haploidentical donor must be available Exclusion Criteria: Prior history of ventilator support related to lung injury, except for immediately following thoracotomy Symptomatic pleural effusions or ascites <6 weeks from thoracotomy and <2 weeks from other major surgery History of anaphylaxis while receiving prior anti-GD2 therapy Pregnant HIV infection Heart failure or uncontrolled cardiac rhythm disturbance Active infection Prior organ allograft Prior allogeneic bone marrow or peripheral blood stem cell transplant Significant serious intercurrent illnesses expected to interfere with the antitumor effect of treatment or to significantly increase the severity of toxicities experienced from treatment Any mental or physical condition, in the opinion of the PI (or PI designee), which could interfere with the ability of the subject (or the only parent or legal guardian available to care for the subject) to understand or adhere to the requirements of the study. Enrollment in any other treatment study from screening up to 28 days after the last treatment on this study (unless PI judges such enrollment would not interfere with endpoints of this study)
