Immunology Research

Biography

Biography: Claudia Gravekamp

Abstract

Our laboratory has built a platform for the selective delivery of anticancer agents to the tumor microenvironment (TME) using a live attenuated bacterium Listeria monocytogenes. We discovered that Listeria could infect and kill tumor cells through reactive oxygen species, and selectively survives and multiplies in tumors and metastases but not in normal tissues because of the strong immune suppression in the TME that is absent in normal tissues. Listeria can infect tumor cells directly or through infection of myeloid-derived suppressor cells (MDSC), which are selectively attracted to the TME through cytokines and chemokines. Once at the tumor site, Listeria efficiently moves from MDSC into tumor cells through a mechanism specific to Listeria. This novel discovery opened doors for the development of complete new therapies, particularly for non-curable metastatic cancers. We developed Listeria-188Rhenium and Listeria-32P. Both have been tested in preclinical models for biodistribution, efficacy, and safety. These radioactive Listeria bacteria strongly reduced the growth of pancreatic cancer at early and advanced stages in various mouse tumor models, with practically no side effects. We also generated Listeria-based vaccines, expressing highly immunogenic “recall antigens” (RA) derived from tetanus toxoid (TT) protein, polio virus (PV) and measle virus (MV), which in combination with low doses of Gemcitabine, resulted in the reactivation of memory T cells to RA (generated during childhood vaccination and circulating in blood for life), now capable of killing Listeria-RA-infected tumor cells, with help of Gemcitabine-reduced immune suppression. These results demonstrate the potential of Listeria as a selective delivery platform for cancer immunotherapy. Delivery of adjuvants, RNAs, apoptotic genes, small molecules by Listeria to the TME could be a promising next step in the fight against metastatic cancer.