A team of investigators at the University of Wisconsin American Family Children’s Hospital are developing a new approach to treating patients with neuroblastoma that has the potential to improve outcomes for patients not responding to standard therapies.
Natural Killer (NK) 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 KN 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 patient’s 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.
A Phase I study, the sponsors seek 6 participants as part of a single group assignment.
Mechanisms of Action
In the trial, the antibody being used is the hu14.18-IL2 immunocytokine (IC). This molecule has several potential advantages compared with the commercially available anti-GD2 mAb ch14.18 (dinutuximab; Unituxin). First, the IC has been humanized and therefore contains less mouse protein, which should reduce the likelihood of eliciting a neutralizing human anti-mouse antibody response. Secondly, the IL-2 component of the IC can help maintain the NK cells in an activated state because IL-2 stimulates NK cell proliferation, increases production of perforin and interferon gamma (IFNγ), upregulates surface expression of NK cell activation receptors such as the natural cytotoxicity receptors (NKp30, NKp44, NKp46), NKG2D, and DNAM-1, and enhances both natural cytotoxicity (ie, antibody independent) and antibody-dependent cellular cytotoxicity (ADCC).
The University of Wisconsin research team has initiated a first-in-human clinical trial for children with relapsed or refractory neuroblastoma, utilizing the combination of an anti-GD2 monoclonal antibody (m AB) and haploidentical ex-vivo activated and expanded natural killer (AE NK).
The goal of this effort is to develop new options for patients with the most challenging forms of neuroblastoma, which is the most common solid tumor of childhood occurring outside the central nervous system.
National Cancer Institute
Solving Kids’ Cancer
Midwest Athletes Against Childhood Cancer, Inc. (MACC Fund)
The Catherine Elizabeth Blair Memorial Foundation/GWCF
Ken DeSantes, MD, University of Wisconsin Carbone Cancer Center