Combating tumor heterogeneity with early cancer detection and immunotherapy
Abstract/Contents
- Abstract
- Tumor heterogeneity refers to the existence of clonal subpopulations of cells within and between neoplastic lesions and is an important driver of tumor progression, resistance to therapy, and relapse. Precision medicine offers one strategy of combating tumor heterogeneity by using genetic information about these subpopulations to inform personalized therapy. Despite notable successes, the degree of heterogeneity in tumors is often too great for this "drug cocktail" approach to be effective, and patients frequently develop refractory or relapsed disease. Here we present an alternative approach to precision medicine, arguing that tumor heterogeneity can best be addressed by either (1) avoiding its emergence with early cancer detection or (2) combating it with equally heterogeneous therapies that leverage the naturally diverse repertoire of the adaptive immune system. To this end, we describe four technologies that address key limitations in the fields of early cancer detection and cancer immunotherapy. Beginning with early cancer detection, we first address the problem of biomarker scarcity by engineering an intravascular system of magnetic enrichment capable of collecting circulating cancer biomarkers from the entire blood volume. We continue by asking how we can overcome low signal-to-noise ratios in cancer liquid biopsies, and we present a method of enriching rare mutant alleles in cell-free DNA to enable more sensitive mutation detection. Acknowledging that there are inherent limitations to early detection using endogenous biomarkers, we also present an engineered immune cell sensor for ultrasensitive tumor detection in living subjects. Finally, we consider how we can leverage the body's natural immune diversity to theoretically cover all neoplastic clonal subpopulations. Using chimeric antigen receptor T-cell therapy and epitope spreading as an example, we present a method of delivering ectopic surface antigens to malignant cells to generate a universal approach to adoptive cell therapy in solid tumors. The approaches detailed in this thesis provide a conceptual framework for how to strategically approach translational cancer research and can inform continued efforts towards reducing the global burden of cancer
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 | Aalipour, Amin |
|---|---|
| Degree supervisor | Gambhir, Sanjiv Sam |
| Thesis advisor | Gambhir, Sanjiv Sam |
| Thesis advisor | Diehn, Maximilian |
| Thesis advisor | Swartz, James R |
| Degree committee member | Diehn, Maximilian |
| Degree committee member | Swartz, James R |
| Associated with | Stanford University, Department of Bioengineering. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Amin Aalipour |
|---|---|
| Note | Submitted to the Department of Bioengineering |
| Thesis | Thesis Ph.D. Stanford University 2020 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Amin Aalipour
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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