Assistant Professor of Pediatrics, University of Pennsylvania Perelman School of Medicine
Attending Physician and Associate Fellowship Director, Pediatric Infectious Diseases, Children’s Hospital of Philadelphia
Faculty Member, Center for Childhood Cancer Research, Children’s Hospital of Philadelphia
2020 TeamConnor Childhood Cancer Foundation research grant recipient
Neuroblastoma is a childhood cancer of the nervous system that often presents at an advanced stage, and portends poor prognosis (typically only about 50-60% 5-year overall survival) even despite recent therapeutic advancements. In order to identify novel immunotherapeutic approaches, my laboratory has been studying the nature of the immune cells that infiltrate the tumors in a preclinical model of aggressive human neuroblastoma. We have demonstrated that certain white blood cells called invariant natural killer T (iNKT) cells infiltrate these neuroblastoma tumors at unexpectedly elevated frequencies. Importantly, we and others had previously established that iNKT cells not only directly kill a variety of tumor cells, but also arm and potentiate the anti-tumor capacities of other immune cells. Consistent with these prior observations, two groups showed that children whose neuroblastoma tumor contained elevated frequencies of iNKT cells had an almost two-fold better chance of survival at 5 years, when compared to children whose tumors had low frequencies of iNKT cells. These findings collectively prompted us to ask two questions: 1) Are iNKT cells particularly suited to the neuroblastoma tumor microenvironment? And 2) Could we trigger the anti-tumor functions of iNKT cells within neuroblastoma tumors?
With respect to question 1, work funded by the foundation has allowed a pre-doctoral candidate in my lab (Ms. Priya Khurana) to elegantly delineate the metabolic pathways that iNKT cells use to persist and function within the neuroblastoma tumor microenvironment. Importantly, her findings demonstrate that the use of these metabolic pathways does not apply to conventional T cells (the white blood cells that are used to generate CAR T cells); this work has very important implications for the cellular immunotherapy of neuroblastoma. With respect to question 2, a pediatric hematology-oncology clinical fellow (Dr. Kevin McNerney) has generated fusion molecules that we call CAbs; these CAbs are designed to bind neuroblastoma tumor cells and iNKT cells and potently activate the antitumor functions of the iNKT cells. Preliminary studies show that iNKT cells are indeed activated by CAbs to kill neuroblastoma tumor cells in a culture dish. Moreover, CAbs also activate iNKT cells that have infiltrated neuroblastoma tumors. Dr. McNerney has now generated a variety of second-generation CAbs that are not only likely to better persist in the host, but also have different binding strengths for neuroblastoma tumor cells and varied capacity for persistent activation of iNKT cells. These various second-generation CAbs will be methodically tested in culture and in our preclinical model of aggressive neuroblastoma to determine the efficacy of this promising approach. We believe that these observations collectively credential the use of iNKT cells in the immunotherapy of neuroblastoma. We are thus extremely grateful to the TeamConnor Childhood Cancer Foundation for funding our studies to answer these critical questions.
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