2026-09-19T22:38:09Zhttps://dspace.mit.edu/server/oai/requestoai:dspace.mit.edu:1721.1/1078722026-06-16T18:14:13Zcom_1721.1_7582com_1721.1_7581col_1721.1_131022
K. Dane Wittrup.
Zhu, Eric F. (Eric Franklin)
Massachusetts Institute of Technology. Department of Chemical Engineering.
Massachusetts Institute of Technology. Department of Chemical Engineering
2017-04-05T16:01:02Z
2017-04-05T16:01:02Z
2016
2016
http://hdl.handle.net/1721.1/107872
976406134
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.
123 pages
eng
Massachusetts Institute of Technology
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
Chemical Engineering.
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
Thesis
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<Abstract>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.</Abstract>
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