In the battle against cancer, therapeutic vaccines are proving to be a promising new approach. Many approaches focus on delivery of therapeutic vaccines via live vectors. However there is still a need to develop novel platform technologies for the production of therapeutic vaccines with defined cancer tumor antigens. We have been actively involved in optimizing the delivery and antigenicity of tumor associated antigens for cancer vaccines for future development of human therapeutics. Paterson et al. have demonstrated that Listeria monocytogenes (Listeria)-delivery of a modified version of the cervical carcimona tumor antigen, E7, permanently cured 50 to 80% of mice with established HPV-16 transformed subcutaneous tumors. The E7 protein was modified by fusing it to the N-terminal PEST (Proline (P), Glutamic Acid (E), Serine (S) and Threonine (T)) containing domain of the listeriolysin O (LLO) protein. The addition of the LLO PEST domain to the tumor antigen significantly enhanced the antigenicity and efficacy of this vaccine. However, in a clinical setting there are safety concerns associated with the use of live vectors, particularly among patients who may be immunocompromised by chemotherapy, radiation or other illness. We propose to examine the feasibility of administering these Listeria virulence factor tumor antigen fusion proteins as protein-based vaccines. We expect the fusion proteins to significantly enhance the immunogenicity and efficacy of tumor antigens in protein-based vaccines. In this Phase 1 proposal Advaxis will demonstrate the feasibility of tumor antigens fused to Listeria virulence factors to serve as effective platforms for protein based cancer vaccines. To that end, we will evaluate the efficacy of a protein therapeutic vaccine consisting of the E7 tumor antigen fused with either the N-terminal PEST-containing domain of the LLO protein or the 396 amino acid PEST-containing domain of the ActA protein at inducing regression of established HPV-16 transformed subcutaneous tumors in mice. Advaxis believes that this novel approach will result in a vaccine platform that can be adapted to different cancers and other diseases and optimized to minimize side effects. This project will set the stage for further drug development in Phase II of the SBIR process, eventually resulting in introduction of novel commercially available therapeutics.
Thesaurus Terms: Listeria, bacterial protein, neoplasm /cancer vaccine, protein sequence, tumor antigen, vaccine development, vaccine evaluation, vector vaccine gene expression, glutamine, human papillomavirus, immunotherapy, neoplastic growth, nonhuman therapy evaluation, proline, protein purification, recombinant protein, serine, threonine Escherichia coli, affinity chromatography, ion exchange chromatography, laboratory mouse, polymerase chain reaction
