Subjects 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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
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.
University of Wisconsin Carbone Cancer Center; UW Hospital and Clinics
Madison, Wisconsin, United States
Safety: Incidence of treatment-emergent adverse events of treatment with AENK cells and hu14.18-IL2
Safety will be assessed by quantifying adverse events ≥ grade 3, using CTCAE (v.5), with certain pre-defined exceptions based on known, transient, reversible, clinically manageable toxicities of the chemotherapy and hu14.18-IL2.
Time frame: up to 28 days after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last
Safety: Incidence of any grade acute or chronic GVHD
Safety will be assessed by monitoring for any grade acute or chronic GVHD.
Time frame: up to 21 days after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last
Efficacy: Progression free survival
The time elapsed from initial EANK cell infusion until disease progression or death or study censure 12 months after final dose of immunotherapy
Time frame: up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last
Efficacy: Overall survival
The time from initial EANK cell infusion until death from any cause or study censure 12 months after final dose of immunotherapy
Time frame: up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last
Efficacy: Objective tumor response (SD + CR + PR)
The anti-tumor effect of treatment will be assessed by quantifying the number of subjects who achieve stable disease, complete remission and partial remission
Time frame: up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last
Longevity of EA-NK cells in vivo
Evaluating the survival of EA-NK cells in the subject using flow cytometric analysis of donor-only antigens
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Time frame: 28 days
Immunocytokine (hu14.18-IL2) serum levels given as daily infusions for 7 consecutive days
Hu14.18-IL2 serum levels will be assessed using ELISA
Time frame: up to 28 days after last hu14.18-IL2 infusion
Immunogenicity of hu14.18-IL2 given as daily infusions for 7 consecutive days
Measurement of anti-hu14.18-IL2 antibodies (HAHA) using ELISA
Time frame: up to 28 days after last hu14.18-IL2 infusion
Proportion and absolute numbers of NK and T cell subsets
NK and T cell subsets will be evaluated using flow cytometric assessment of cell phenotype expressed as percentages of larger cell subsets and absolute numbers.
Time frame: up to 22 days after the third EANK cell infusion for subjects in Cohort A and up to 22 days after the second EANK cell infusion for subjects in Cohort B
EANK cell survival in vivo
The longevity of EANK cells in vivo (i.e., after infusion) will be assessed by evaluating donor-specific HLA markers present on NK cells using flow cytometry
Time frame: up to 22 days after the third EANK cell infusion for subjects in Cohort A and up to 22 days after the second EANK cell infusion for subjects in Cohort B
NK cell activity
The functional status of NK cells will be measured: 1) indirectly by assessing NK activation receptor expression and NK exhaustion marker expression using flow cytometric analyses and 2) directly by measuring the ability of NK cells to kill tumor cells in vitro
Time frame: up to 22 days after the third EANK cell infusion for subjects in Cohort A and up to 22 days after the second EANK cell infusion for subjects in Cohort B