Engineering immunity : enhancing T Cell vaccines and combination immunotherapies for the treatment of cancer
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2017.
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| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2018
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| Online Access: | http://hdl.handle.net/1721.1/113960 |
| _version_ | 1826191398694551552 |
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| author | Moynihan, Kelly D. (Kelly Dare) |
| author2 | Darrell J. Irvine. |
| author_facet | Darrell J. Irvine. Moynihan, Kelly D. (Kelly Dare) |
| author_sort | Moynihan, Kelly D. (Kelly Dare) |
| collection | MIT |
| description | Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2017. |
| first_indexed | 2024-09-23T08:55:35Z |
| format | Thesis |
| id | mit-1721.1/113960 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T08:55:35Z |
| publishDate | 2018 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/1139602022-01-13T07:53:54Z Engineering immunity : enhancing T Cell vaccines and combination immunotherapies for the treatment of cancer Moynihan, Kelly D. (Kelly Dare) Darrell J. Irvine. Massachusetts Institute of Technology. Department of Biological Engineering. Massachusetts Institute of Technology. Department of Biological Engineering Biological Engineering. Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2017. Cataloged from PDF version of thesis. Includes bibliographical references (pages 127-140). Checkpoint blockade with antibodies against CTLA-4 or PD-1 has demonstrated that an endogenous adaptive immune response can be stimulated to elicit durable tumor regressions in metastatic cancer, but these dramatic responses are confined to a minority of patients¹-³. This outcome is likely due in part to the complex network of immunosuppressive pathways present in advanced tumors, which necessitates the development of novel therapeutics and combination immunotherapies to generate a counter-directed network of pro-immunity signals⁴-⁸. In Chapters 2 and 3 of this thesis, we describe methods for enhancing T cell priming against tumor antigens via covalent modification of molecular vaccines to enhance lymphatic drainage, serum stability, or cytosolic access to improve presentation on MHC class I. In Chapter 4, we demonstrate a combination immunotherapy that recruits a diverse set of innate and adaptive effector cells, enabling robust elimination of large tumor burdens that to my knowledge have not previously been curable by treatments relying on endogenous immunity. Maximal anti-tumor efficacy required four components: a tumor antigen targeting antibody, an extended half-life IL-2⁹, anti-ƯPD-1, and a powerful T-cell vaccine¹⁰. This combination elicited durable cures in a majority of animals, formed immunological memory in multiple transplanted tumor models, and induced sustained tumor regression in an autochthonous BRraf[superscript V600E]/Pten[superscript -/-] melanoma model. Finally, in Chapter 5, we show preliminary data on combination immunotherapies used to treat antigenically heterogeneous tumors. Taken together, these data define design criteria for enhancing the immunogenicity of molecular vaccines and elucidate essential characteristics of combination immunotherapies capable of curing a majority of tumors in experimental settings typically viewed as intractable. "During my doctorate by the John and Fanny Hertz Foundation Fellowship (specifically the Wilson Talley Hertz Fellowship), the NSF Graduate Research Fellowship Program, and the Siebel Scholarship"--Page 141. "This thesis work was supported in part by the Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute, the US National Institutes of Health (NIH) grant CA174795, the Bridge Project partnership between the Koch Institute for Integrative Cancer Research and the Dana Farber-Harvard Cancer Center (DF-HCC), the V Foundation, the Ragon Institute, and the Howard Hughes Medical Institute"--Page 141. by Kelly D. Moynihan. Ph. D. 2018-03-02T22:20:40Z 2018-03-02T22:20:40Z 2017 2017 Thesis http://hdl.handle.net/1721.1/113960 1023498072 eng MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission. http://dspace.mit.edu/handle/1721.1/7582 153 pages application/pdf Massachusetts Institute of Technology |
| spellingShingle | Biological Engineering. Moynihan, Kelly D. (Kelly Dare) Engineering immunity : enhancing T Cell vaccines and combination immunotherapies for the treatment of cancer |
| title | Engineering immunity : enhancing T Cell vaccines and combination immunotherapies for the treatment of cancer |
| title_full | Engineering immunity : enhancing T Cell vaccines and combination immunotherapies for the treatment of cancer |
| title_fullStr | Engineering immunity : enhancing T Cell vaccines and combination immunotherapies for the treatment of cancer |
| title_full_unstemmed | Engineering immunity : enhancing T Cell vaccines and combination immunotherapies for the treatment of cancer |
| title_short | Engineering immunity : enhancing T Cell vaccines and combination immunotherapies for the treatment of cancer |
| title_sort | engineering immunity enhancing t cell vaccines and combination immunotherapies for the treatment of cancer |
| topic | Biological Engineering. |
| url | http://hdl.handle.net/1721.1/113960 |
| work_keys_str_mv | AT moynihankellydkellydare engineeringimmunityenhancingtcellvaccinesandcombinationimmunotherapiesforthetreatmentofcancer |