Dr. Yvonne Paterson, Ph.D., Professor of Microbiology, Perelman School of Medicine & Associate Dean for Research and Professor at the University of Pennsylvania School of Nursing
Listeria monocytogenes Developing A Perfect Vector for Cancer Immunotherapy
- Yvonne Paterson, PhD, professor of microbiology at the Perelman School of Medicine, and associate dean for research and professor at the University of Pennsylvania School of Nursing, as well as the scientific developer of Advaxis’s immunotherapy platform, discussed in-depth her discovery of the Listeria monocytogenes (Lm) vector and the development process her laboratory used to create the unique Lm-listeriolysin O (LLO) immunotherapy platform used today in clinical trials
- Dr Paterson concisely described the 4 elements of a successful cancer immunotherapy, including efficient and precise integration of tumor antigen into the host antigen-presenting cell (APC), rapid generation of a host T-cell response to the tumor antigen, a mechanism to bypass negative regulators or host immune response checkpoints, and a means to generate a “friendly” tumor microenvironment (TME) that allows the newly tumor-targeted T cells to do their job and fight the cancer.
- Dr Paterson further explained “why Lm-LLO”?
- The right bacteria – Attenuated (virulence factor-depleted) Lm specifically infects APCs and its innate LLO enzyme allows it to enter the cytosol of these cells, unscathed, and deliver its payload into the host system
- The best method for vector transformation – The most effective transformation of the Listeria from opportunistic bacteria to targeted tumor antigen vector is by using multi-copy plasmids, as opposed to insertion of a single gene copy into the bacterial chromosome backbone. Multi-copy plasmid transformation not only ensures more copies of the antigen are released in the APC, but also contributes to Listeria virulence attenuation.
- The ideal promoter to drive antigen expression – LLO is the promoter of choice because it stimulates early production of the antigen release while inside the phagolysosome, as well as following entry into the cell cytosol.
- The fusion protein partner – When the naked antigen vector is fused to an effective protein adjuvant, its ability to manipulate the TME, reduce the immunosuppressive effects of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and thereby stimulate the innate immune system is markedly enhanced. LLO is not only the ideal promoter, but has also proven to be the most effective fusion protein to elicit antitumor activity.
- A rational tumor antigen – The tumor antigen vector must be selectively expressed in tumor vs normal human tissues, contribute to the malignant phenotype, and be retained under immune pressure. Human papilloma virus (HPV), human epidermal growth factor receptor 2 (HER2), and prostate-specific antigen (PSA) meet these criteria.
- In summary, Lm-LLO immunotherapies are highly attenuated and non-pathogenic, are constructed to serve as their own adjuvant with the concomitant ability to favorably modify the TME, and have demonstrated single-agent antitumor activity in humans with diverse cancers.