Advisory Committee Chair
Braden C McFarland
Advisory Committee Members
Elizabeth A Beierle
Timothy W King
Jianmei W Leavenworth
Craig L Maynard
Christopher D Willey
Document Type
Dissertation
Date of Award
2023
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Pediatric cancer is the leading cause of death by disease in children, and neuroblastoma accounts for roughly 15% of pediatric cancer related deaths. Neuroblastoma is a malignancy of neural crest origin and develops in the ganglia of the peripheral nervous system, most commonly arising in the adrenal glands. Advancements in therapy have significantly improved outcomes for children with low-risk neuroblastoma but for those with high-risk refractory, or relapsed disease, survival outcomes remain dismal and intervention with toxic chemotherapeutics often result in long term morbidities. The need for improved therapies for this patient population is dire. Immunotherapies offer a novel approach and have been successful in hematologic malignancies. Unfortunately, this success has not translated to pediatric solid tumors; likely due to the immunosuppressive tumor microenvironment that acts as a barrier to these therapies. Our lab has published data demonstrating an oncolytic Herpes Simplex Virus (oHSV), M002, is an effective therapy that actively replicates within and kills long-term passage neuroblastoma cell lines, however, it has yet to be tested in the more clinical representative preclinical model, patient derived xenografts (PDXs). Furthermore, M002 has been genetically modified, and a gene coding murine interleukin (mIL)-12 has been inserted in attempts to stimulate a more robust immune response aimed toward the immunoreactive debris field created by the virus. We hypothesized that the immunoreactive iv properties of M002 could overcome the barriers of the tumor microenvironment (TME) to improve the natural killer (NK) cell response to neuroblastoma. In this dissertation, we developed a cutting-edge three-dimensional bioprinting model of neural crest-derived tumors that we utilized for studies of M002 in PDXs. We found significant tumor death of PDX bioprinted tumors treated with M002 with substantial mIL- 12 and viral production surrounding the tumor. These prompted our investigation of NK cell fate after exposure to M002 infected neuroblastoma tumor cells. We found that M002 in combination with the NK cell line, NK-92 MI, results in more tumor cell death in vivo than either agent alone. These studies also led us to the discovery of an NK cell’s ability to be primed by neuroblastoma, or neuroblastoma that was infected with M002. We demonstrated that enhanced cytotoxicity of primed NK cells was a result of increased granzyme B release. Additionally, we found that the cell surface expression of an NK cell activating ligand, RAET1E, is likely dependent on MYCN and its cell surface expression increases in a MYCN amplified cell line. The work outlined in this dissertation offers foundational applications to translating therapies, such as oHSV, from the pre-clinical setting to the clinical arena while providing fundamental knowledge on the biology of the NK and neuroblastoma cell interaction. These findings ultimately support the use of oHSV in tandem with exogenous NK cells for combinatorial therapy in treating neuroblastoma.
Recommended Citation
Quinn, Colin Harrington, "Understanding the Dual Role of the Oncolytic Viruses and Natural Killer Cells in Targeting Neuroblastoma" (2023). All ETDs from UAB. 381.
https://digitalcommons.library.uab.edu/etd-collection/381