Optimization of CAR-Bacteria for Oral Cancer
NIH
UNIVERSITY OF CALIFORNIA, SAN DIEGO
ABSTRACT  The goal of this project is to explore the feasibility of generating Chimeric Antigen Receptors (CARs) expressed by bacteria. Instead of using T cells, we propose to explore the idea and use of bacteria to mediate the targeted destruction of cancer cells. In addition, we explore the possibility that we could target CAR-bacteria to specific major histocompatibility complex (MHC)-neopeptide complexes (pMHC) on tumor cells. We call these engineered bacteria cells CAR-bacteria. Current CAR-expressing T cells provide durable responses but have three main limitations: specificity, toxicity, and feasibility. This study will address all three concerns. In this proposal, we target engineered bacterial lysis to head and neck or cervical cancer cells expressing HLA-A2-E7, a known pMHC on tumor cells infected by human papilloma virus (HPV). The targeting enables anti-tumor protein production only when a predefined population density of bacteria is reached. This method should dramatically reduce bacterial colony size and greatly lowers/prevents systemic toxicities. The approach has the potential to be a therapeutic in HPV-positive oral cancer as it could be administered and controlled as a bacterial mouthwash. This project combines two innovations leveraging a Synthetically-Evolved Nanobody (SEN) library proven capable of selectively binding MHC-peptide complexes and combining this specific cancer cell targeting with synchronized circuit lysis to create CAR-bacteria. Our proposed studies provide proof-of-concept that (1) CARs can be produced that recognize pMHC, (2) CAR-bacteria localization and colonization can be controlled by tumor expression of certain pMHC and (3) CAR-bacteria have therapeutic activity against tumor cells that express specific pMHC. We accomplish these proof-of-concept studies via the following two objectives: (1) Optimize binding and specificity of CAR-bacteria to HLA-A2-E7 and (2) Check efficacy of CAR-bacteria in an animal model of head and neck and cervical cancer. NARRATIVE  This project explores the possibility of creating Chimeric Antigen Receptor bacteria (CAR-bacteria) that can be used to target and destroy cancer cells. We combine the expertise of nanobody-mediated targeting (Chang), cancer immunology (Bui), and a synchronized lysis circuit (Hasty) to create truly novel “bugs as drugs”. Future studies could optimize the circuitry, recognition, and payload in the bacteria to provide even higher therapeutic efficacy.
Non-SBIR/STTR