New Antibody-Cytokine Fusion Proteins for the Therapy of Neuroblastoma
Abstract
I am a pediatric oncologist and PhD graduate who aspires to pursue a career as a physician-scientist in the field of neuroblastoma. My interest in neuroblastoma arose during my clinical training, while caring for children afflicted with this debilitating cancer. The most significant breakthrough in the care of patients with neuroblastoma was the incorporation of immunotherapy into the current standard of care. Although immunotherapy significantly extended the survival of affected children, little was known about the mechanism that was underlying this clinical observation. Thus, in my PhD, my research gravitated towards the study of basic mechanisms involved in immune destruction of neuroblasts by means of immunotherapy. While trying to better understand these basic processes, I also tested therapeutic strategies to enhance the current immunotherapy in my experiments. These will now be incorporated into upcoming clinical trials at St. Jude Children’s Research Hospital. In the future, my overall research aim is to find more efficient immunotherapies for the treatment of neuroblastoma. Specifically, I want to determine the role of cytokines in maximizing inherent cell-mediated immunity of patients as a cancer fighting modality. Therefore, to broaden my training in immunology with emphasis on cytokine research, I joined the laboratory of Dr. Warren J. Leonard at the National Institutes of Health. Because neuroblastoma is not necessarily the primary focus of the current laboratory, allocation of funds obtained from the Fiscal Year 2019 Peer Reviewed Cancer Research Program Horizon Award toward the proposed studies herein would be paramount for achieving the stated research objectives. Altogether, my previous research experiences, as well as the successful realization of this project, will allow me to launch my research career in the field of neuroblastoma. Neuroblastoma, the most common extracranial solid malignancy of childhood, accounts for 12% of all cancer-related deaths in pediatrics. Historically, children with high-risk neuroblastoma had a very poor prognosis despite multi-modal therapies. However, immunotherapy with an antibody that specifically recognizes disialoganglioside (GD2) on the cell surface of neuroblasts and interleukin (IL)-2 has significantly improved the survival in these patients. Nevertheless, the benefit of IL-2 has remained questionable owing to severe toxicities and unestablished efficacy. In addition, one-third of patients experience therapy failure within the first 2 years of therapy. To improve immunotherapy for neuroblastoma, an anti-GD2 antibody and IL-2 fusion protein was engineered (hu14.18-IL-2) that induced tumor regression in 16%-22% of patients with relapsed/refractory neuroblastoma enrolled in a phase II clinical trials. In one of these studies, more than 90% of the patients experienced toxicity and bulky tumors did not respond. I recently demonstrated that substituting IL-15 for IL-2 in a current neuroblastoma immunotherapy regimen resulted in more tumor shrinkage in mice with bulky tumors, conceivably by promoting differentiation of tumor-infiltrating immune cells called natural killer (NK) cells. These cells are implied in the process of tumor cell destruction with antibody therapy. IL-21 is known to also activate NK cells but has not been a major focus of investigation in neuroblastoma. Thus, I propose to engineer and test two novel antibody-cytokine fusion proteins, namely anti-GD2 antibody linked to IL-15 or IL-21, and compare them with hu14.18-IL-2. I hypothesize that these new antibody-cytokine fusion proteins can cause equivalent or higher tumor regression than hu14.18-IL-2. Secondly, I believe that the enhanced activity against neuroblastoma is caused by changes in the gene and protein cell surface expression of tumor-infiltrating immune cells. These hypotheses will be tested in cell culture and contemporary animal models. The proposed experiments have the potential of di
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010888
Entities
People
- Hong Ha Rosa Nguyen
Organizations
- National Cancer Institute
- United States Army