Hurdles to targeting the CD47-SIRP-alpha interaction for immunotherapy
Abstract/Contents
- Abstract
- The CD47-SIRPα signaling pathway has emerged as an important innate immune checkpoint axis, with CD47 acting as a marker of self and health. Numerous cancers have been shown to upregulate CD47 expression, including hematologic cancers such as acute myeloid leukemia (AML) and non-Hodgkin's lymphoma (NHL), and myeloma, and solid tumors such as ovarian cancer, breast cancer, head and neck cancers, colon cancer, pancreatic neuroendocrine tumors, small lung cell cancer, and glioblastoma. The number of pharmaceutical companies and startups developing therapies which target this immune axis has grown exponentially in the past decade. At the forefront are antibodies which bind CD47 and interrupts its binding to SIRPα. The biggest challenges to targeting CD47 are the on-target effects on red blood cells and platelets, both of which depend on cell surface CD47 to avoid phagocytosis. Patients receiving treatments suffer from anemia and thrombocytopenia. Additionally, it remains unclear if other types of healthy cells rely solely on CD47 as a "don't eat me" signal and are subject to depletion like RBCs and platelets. Another hurdle is one that plagues all therapies -- heterogeneity in response within the human population. Further understanding of the CD47-SIRPα pathway is necessary to identify the patients that can benefit the most from treatment. The goal of this thesis is to explore some of these hurdles to inform future decisions that can impact patient health. This thesis will show that marginal zone B cells is another population of cells of the hematopoietic lineage that are depleted during CD47 blockade. It further shows that polymorphisms in SIRPΑ might partially explain some of the heterogeneity seen in response to CD47 immunotherapy and might also regulate platelet numbers and size, with implications for thrombocytopenia, stroke and coronary disease. These findings should initiate new avenues of research which will ultimately give a better understanding of the impact of on-target treatment-related adverse events and genetic variations on therapies targeting the CD47-SIRPα axis.
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 | 2022; ©2022 |
| Publication date | 2022; 2022 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Yiu, Ying Ying |
|---|---|
| Degree supervisor | Weissman, Irving L |
| Thesis advisor | Weissman, Irving L |
| Thesis advisor | Blish, Catherine |
| Thesis advisor | Shizuru, Judith Anne |
| Thesis advisor | Sunwoo, John B |
| Degree committee member | Blish, Catherine |
| Degree committee member | Shizuru, Judith Anne |
| Degree committee member | Sunwoo, John B |
| Associated with | Stanford University, Department of Immunology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Ying Ying Yiu. |
|---|---|
| Note | Submitted to the Department of Immunology. |
| Thesis | Thesis Ph.D. Stanford University 2022. |
| Location | https://purl.stanford.edu/zw987kx2998 |
Access conditions
- Copyright
- © 2022 by Ying Ying Yiu
- License
- This work is licensed under a Creative Commons Attribution Non Commercial Share Alike 3.0 Unported license (CC BY-NC-SA).
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