Intra-tumoral Injection of Natural Killer Cells in High-Grade Gliomas
Intra-tumoral Injection of Natural Killer Cells in High-Grade Gliomas
Patients will receive 3 cycles of NK cell infusions over 12 weeks. Each cycle will consist of
 1 infusion per week for 3 weeks, followed by a rest week (week 4). Dose will be escalated in
 an inter-patient stepwise fashion consisting of 4 dose levels.
Patient enrollment will follow a 3+3 design. Patients will receive 3 cycles of NK cell
 infusions over 12 weeks. Each cycle will consist of 1 infusion per week for 3 weeks, followed
 by a rest week (week 4). Dose will be escalated in an inter-patient stepwise fashion
 consisting of 4 dose levels until dose limiting toxicities are observed or the recommended
 phase II dose is determined.
Inclusion Criteria:

 1. Patients must have a histologically-confirmed recurrent non-metastatic supratentorial
 WHO Grade III malignant glioma (anaplastic astrocytoma, anaplastic oligoastrocytoma,
 anaplastic oligodendroglioma, and anaplastic pleomorphic xanthoastrocytoma) or WHO
 Grade IV malignant glioma (glioblastoma multiforme, gliosarcoma, malignant glioma NOS)

 2. Patients should be candidates for resection/open biopsy of the recurrent tumor and be
 deemed candidate for placement of an Ommaya reservoir placed intra-cavitary/
 intra-tumoral; measurable residual tumor after surgery is not required for study entry

 3. Given the lack of a standard of care treatment for children with recurrent grade
 III/IV gliomas, patients must have completed first-line treatment with 54 Gy of
 radiation prior to participating in this trial

 4. All patients must be ≥ 3 years of age and <18 years of age at the time of study entry
 into the study

 5. Lansky score of 50 or greater if ≤ 16 years of age or a Karnofsky score of 50 or
 greater if >16 years of age

 6. Adequate bone marrow function, without transfusion or growth factors within 21 days of
 NK cell administration, defined as a white blood cell ≥ 2.5 x 103/microliter,
 hemoglobin ≥ 9 gm/dL, absolute neutrophil count ≥ 1,000 cells/microliter and platelet
 count of ≥ 75,000 cells/microliter

 7. Patients must be off systemic steroids (except replacement therapy) for at least 3
 days prior to NK cell infusion

 8. Adequate liver function (ALT, AST and alkaline phosphatase < 2 times ULN, bilirubin <
 1.5 times ULN), and adequate renal function (BUN or creatinine < 1.5 times ULN) prior
 to NK cell

 9. Must have recovered from the toxic effects of prior therapy (i.e., NCI-CTCEA version 5
 grade 1 or less) 9a. An interval of at least 12 weeks must have elapsed since the
 completion of initial radiation therapy 9b. At least 6 weeks since the completion of
 any cytotoxic chemotherapy regimen 9c. For targeted agents only, patient should have
 recovered from any toxicity of the agent and have a minimum of 2 weeks since the last
 dose 9d. For patients who have received prior bevacizumab, at least 6 weeks is
 required before starting study treatment

 10. Patients of child-bearing potential must agree to use adequate contraception (hormonal
 or barrier method of birth control or abstinence) prior to study entry and for six
 months following duration of study participation

 Exclusion Criteria:

 1. Patients with intra- or extra-CNS metastasis

 2. Tumor involvement that would require ventricular, brainstem or posterior fossa
 injection or access through a ventricle or risk of ventricular penetration in order to
 deliver the NK cells

 3. Tumors involving both hemispheres or those involving the subependyma or suspected CSF
 dissemination

 4. Patients undergoing needle biopsies (Open biopsies are the minimum requirement for
 enrollment)

 5. Pregnant or lactating patients

 6. Patients on chronic corticosteroid therapy (except for replacement therapy)

 7. Evidence of active uncontrolled infection or unstable or severe intercurrent medical
 conditions. All subjects must be afebrile at baseline (i.e., < 38.0 Celsius [C])

 8. Any medical condition that precludes surgery

 9. Prothrombin time/international normalized ratio (PT/INR) or partial thromboplastin
 time (PTT) > 1.5 x ULN

 10. Patients with a known disorder that affects their immune system, such as human
 immunodeficiency virus (HIV), or an auto- immune disorder requiring systemic cytotoxic
 or immunosuppressive therapy are not eligible

 11. Evidence of bleeding diathesis or use of anticoagulant medication or any medication
 which may increase the risk of bleeding. If the medication can be discontinued >1 week
 prior to NK cell infusion then the subject may be eligible following consultation with
 the principal investigator (PI)

 12. Subjects with significant systemic or major illnesses including but not limited to:
 congestive heart failure, ischemic heart disease, kidney disease or renal failure,
 organ transplantation, or significant psychiatric disorder

 13. History or current diagnosis of any medical or psychological condition that in the
 Investigator's opinion, might interfere with the subject's ability to participate or
 inability to obtain informed consent because of psychiatric or complicating medical
 problems