Dutton, Selena, 2021-2022

Selena
Selena
Dutton

Host Mentor: Dr. Michelle Monje
Stanford Institute for Stem Cell Biology and Regenerative Medicine

Diffuse intrinsic pontine gliomas (DIPG) are the leading cause of childhood brain cancer-related deaths and have limited therapeutic options. A novel approach to treating DIPG is CAR T-cell therapy, a therapy already in use for acute lymphoblastic leukemia (ALL). Patients that undergo CAR T-cell therapy often experience important side effects, including cognitive dysfunction. Here we sought to understand how cancer immunotherapy impairs cognition, and how to restore cognition following CAR T-cell therapy. Microglial activation and consequent dysregulation of neural precursor cells is a known mechanism of impaired cognition after cancer therapies. Colony stimulating factor 1 receptor (CSF1R) is exclusively expressed on microglia and CSF1 signaling is required for microglial survival. The use of a CSF1R inhibitor (PLX5622)  depletes microglial and restores cognition after cancer chemotherapy by restoring neural precursor cell function. Patient-derived cancer cells were xenografted into mice. Mice were later injected with GD2 CAR T-cell therapy (to treat DIPG xenografts), CD19 CAR T-cell treatment (to treat ALL), or control. 2 weeks after CAR T-cell therapy, PLX5622 was administered orally for 2 weeks to deplete microglia and other myeloid cells. A novel object recognition test (NORT) was performed to test cognitive function, cerebral spinal fluid was collected for cytokine analysis, then mice were euthanized and brains were collected for immunohistochemistry. We found activated microglia in the same pattern observed after cancer chemotherapy, together with impairment in hipocampal neural precursor cell and oligodendrocyte precursor cell function, leading to impaired myelination and reduced hippocampal neurogenesis. We found the use of PLX5622 reduced activated microglia. NORT revealed that CSF1R inhibition restored cognition in CD19-CAR T-cell treatment groups, indicating PLX5622 has potential to restore cognition in cancer patients. Similar testing is ongoing in models of CAR T cell therapy for DIPG. We can conclude that CSF1R inhibition decreases activated microglia, improved neural precursor cell function and restores cognition in mice receiving CD19-CAR T-cell treatment for ALL. Understanding the implications of CAR T-cell therapy allows for possible restoration of cognition by microglial modulation for long-term survivors of cancer  immunotherapy.