Synergistic anti-tumor immune response to combination immunotherapy consisting of anti-tumor antibodies, extended half-life Interleukin-2, and other immunomodulatory agents
| Autor: | Zhu, Eric F. (Eric Franklin) |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: | |
| Druh dokumentu: | Diplomová práce |
| Popis: | 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. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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