In 1867, Dr. Wilhelm Busch decisively exposed a cancer patient to erysipelas and notedtumor regression. The practice of inoculating tumors with bacteria became more widespread with the work of Dr. William Coley, beginning in 1891, who inoculated inoperable tumors and observed complete regressions though at times notable toxicity. These microbial manipulations of immunity now form the roots of cancer immunotherapy in modern history. Alongside the blossoming of cancer immunology since, the development of techniques to alter biological systems has given rise to synthetic biology. Together, these fields allow the programming of biological systems to precisely guide the cancer-immune interplay. As mammalian immunity targets bacterially-derived antigens due to the immunostimulatory nature of microbes, and tumors express various antigens, synthetic alteration of microbes to function as safe and effective anti-tumor vaccines is a natural proposition.
In this work, I describe my development of such a microbial system comprised of a synthetic tumor-antigen construct optimized for expression in bacteria, the immunotoxin Listerolysin O, and a genetically edited probiotic E. coli chassis with multi-functional protease deletions. This platform encodes and delivers high levels of diverse tumor antigens sets, remodels the tumor microenvironment, and stimulates productive and durable anti-tumor immunity to control and eliminate primary and metastatic tumors.
We show that this system induces tumor antigen-specific CD4+ and CD8+ T cells, activates NK cells, recruits and activates dendritic cells, and reduces immunosuppressive regulatory T cells, B cells, and myeloid cells within the tumor microenvironment. This work thus establishes a new class of anti-tumor vaccine which modulates all arms of immunity to achieve robust anti-tumor efficacy.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/abtd-0k74 |
| Date | January 2024 |
| Creators | Redenti, Andrew |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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