Synergistic anti-tumor immune response to combination immunotherapy consisting of anti-tumor antibodies, extended half-life Interleukin-2, and other immunomodulatory agents
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2016.
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| Formato: | Tese |
| Idioma: | eng |
| Publicado em: |
Massachusetts Institute of Technology
2017
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| Acesso em linha: | http://hdl.handle.net/1721.1/107872 |
| _version_ | 1826215656323809280 |
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| author | Zhu, Eric F. (Eric Franklin) |
| author2 | K. Dane Wittrup. |
| author_facet | K. Dane Wittrup. Zhu, Eric F. (Eric Franklin) |
| author_sort | Zhu, Eric F. (Eric Franklin) |
| collection | MIT |
| description | Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2016. |
| first_indexed | 2024-09-23T16:37:22Z |
| format | Thesis |
| id | mit-1721.1/107872 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T16:37:22Z |
| publishDate | 2017 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/1078722019-04-12T16:25:54Z Synergistic anti-tumor immune response to combination immunotherapy consisting of anti-tumor antibodies, extended half-life Interleukin-2, and other immunomodulatory agents synergistic anti-tumor immune response to combination immunotherapy consisting of anti-tumor antibodies, serum-persistent Interleukin-2, and other immunomodulatory agents Zhu, Eric F. (Eric Franklin) K. Dane Wittrup. Massachusetts Institute of Technology. Department of Chemical Engineering. Massachusetts Institute of Technology. Department of Chemical Engineering. Chemical Engineering. Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2016. Cataloged from PDF version of thesis. Includes bibliographical references (pages 109-123). Cancer immunotherapies under development have generally focused on either stimulating T-cell immunity or driving antibody-directed effector functions of the innate immune system such as antibody-dependent cell-mediated cytotoxicity (ADCC). However, as our understanding of antitumor immune responses grows, it has become increasingly apparent that single agent therapies may be insufficient to effectively stimulate all aspects of a complex robust anti-tumor response in a large proportion of patients. Thus, rational combination of single agent immunotherapies has become an area of increasing interest. In this work, we find that a combination of an anti-tumor antigen antibody and an untargeted IL-2 fusion protein with delayed systemic clearance induces significant tumor control in aggressive isogenic tumor models via a concerted innate and adaptive response. We find that this therapy induces the infiltration of various immune effectors such as neutrophils, eosinophils NK cells, and CD8+ T-cells that appear to direct cytolytic activity against tumor cells. This combination therapy also induces an intratumoral "cytokine storm," potentially re-polarizing the tumor microenvironment into one that is immunologically anti-tumor. We also identify cross-talk between NK cells and macrophages to induce intratumoral recruitment of neutrophils but with the requisite presence of anti-tumor antibodies and IL-2 simultaneously. We further enhanced the efficacy of this two-component therapy with the addition of a potent amphiphile-based anti-tumor peptide vaccine in combination with checkpoint blockade of anti-PD-I and anti-CTLA-4. This multi-component therapy was tested in a setting of a low-mutational burden GEM lung cancer model with a single known and targetable antigen: human carcinoembryonic antigen (CEA). We find that in the subcutaneous setting and autochthonous setting, both components of checkpoint blockade are necessary for full efficacy. While a 5- component therapy is admittedly unwieldy for clinical translation, understanding the complementary yet non-overlapping contributions of each agent may inform improved development of additional immunotherapy agents and their combinations in the clinic. by Eric F. Zhu. Ph. D. 2017-04-05T16:01:02Z 2017-04-05T16:01:02Z 2016 2016 Thesis http://hdl.handle.net/1721.1/107872 976406134 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 123 pages application/pdf Massachusetts Institute of Technology |
| spellingShingle | Chemical Engineering. Zhu, Eric F. (Eric Franklin) Synergistic anti-tumor immune response to combination immunotherapy consisting of anti-tumor antibodies, extended half-life Interleukin-2, and other immunomodulatory agents |
| title | Synergistic anti-tumor immune response to combination immunotherapy consisting of anti-tumor antibodies, extended half-life Interleukin-2, and other immunomodulatory agents |
| title_full | Synergistic anti-tumor immune response to combination immunotherapy consisting of anti-tumor antibodies, extended half-life Interleukin-2, and other immunomodulatory agents |
| title_fullStr | Synergistic anti-tumor immune response to combination immunotherapy consisting of anti-tumor antibodies, extended half-life Interleukin-2, and other immunomodulatory agents |
| title_full_unstemmed | Synergistic anti-tumor immune response to combination immunotherapy consisting of anti-tumor antibodies, extended half-life Interleukin-2, and other immunomodulatory agents |
| title_short | Synergistic anti-tumor immune response to combination immunotherapy consisting of anti-tumor antibodies, extended half-life Interleukin-2, and other immunomodulatory agents |
| title_sort | synergistic anti tumor immune response to combination immunotherapy consisting of anti tumor antibodies extended half life interleukin 2 and other immunomodulatory agents |
| topic | Chemical Engineering. |
| url | http://hdl.handle.net/1721.1/107872 |
| work_keys_str_mv | AT zhuericfericfranklin synergisticantitumorimmuneresponsetocombinationimmunotherapyconsistingofantitumorantibodiesextendedhalflifeinterleukin2andotherimmunomodulatoryagents AT zhuericfericfranklin synergisticantitumorimmuneresponsetocombinationimmunotherapyconsistingofantitumorantibodiesserumpersistentinterleukin2andotherimmunomodulatoryagents |