Targeting the disialoganglioside GD2 with chimeric antigen receptor T cells for immunotherapy in diffuse midline gliomas and exploration of neuron-opc synaptic connectivity in the context of adaptive myelination
Abstract/Contents
- Abstract
- Histone 3 K27M mutated diffuse midline glioma (H3K27M DMG) is a universally fatal pediatric brain tumor. Despite improved understanding of the molecular origins of this disease, translations to improvement in clinical outcomes have yet to materialize. To date, there has been little target exploration for immunotherapy applications in H3K27M DMG. In this thesis, I describe my work that elucidated substantial preclinical efficacy of chimeric antigen receptor (CAR)-bearing T cells targeting the disialoganglioside GD2 as an immunotherapy regimen in patient-derived orthotopic xenograft models of H3K27M DMG. Single-dose systemic administration of GD2-4-1BB-CAR T cells in multiple orthotopic xenograft models of H3K27M DMG achieves potent and lasting antitumor efficacy, including tumor clearance by in vivo bioluminescence imaging and follow-up histology. Treatment-associated toxicity was transient and generally tolerated during the period of peak anti-tumor activity in brainstem orthotopic xenografts. If these results are predictive of human response, GD2-directed CAR T cell therapy in the setting of careful clinical management could have a transformative impact upon H3K27M DMG outcomes. In part two of this thesis, I present data revealing a brain-wide map of afferent neuronal connectivity to oligodendrocyte precursor cells (OPCs). Neurons form bona fide synapses with oligodendrocyte precursor cells (OPCs), but the circuit context of these neuron to OPC synapses remains incompletely understood. Using monosynaptically-restricted rabies virus tracing of OPC afferents, I identified extensive afferent synaptic inputs to OPCs residing in secondary motor cortex and underlying corpus callosum of adult mice. These inputs primarily arise from functionally-interconnecting cortical areas and thalamic nuclei, demonstrating that OPCs in motor-associated territories have synaptic access to brain-wide projection networks engaged in planning and execution of motor tasks. This circuit map is a foundational tool for future studies of context-specific neuron-OPC synapse function
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2020; ©2020 |
| Publication date | 2020; 2020 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Mount, Christopher |
|---|---|
| Degree supervisor | Monje-Deisseroth, Michelle |
| Thesis advisor | Monje-Deisseroth, Michelle |
| Thesis advisor | Mackall, Crystal |
| Thesis advisor | Malenka, Robert C |
| Thesis advisor | Palmer, Theodore W |
| Degree committee member | Mackall, Crystal |
| Degree committee member | Malenka, Robert C |
| Degree committee member | Palmer, Theodore W |
| Associated with | Stanford University, Neurosciences Program. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Christopher W. Mount |
|---|---|
| Note | Submitted to the Neurosciences Program |
| Thesis | Thesis Ph.D. Stanford University 2020 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Christopher Mount
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...