# Design of Outer Membrane Vesicles as Cancer Vaccines: A New Toolkit for Cancer Therapy
## 3 New OMV Applications: Tumor Vaccines  
### Roles of OMVs as Vaccines  
OMVs are naturally released by Gram-negative bacteria; they mainly comprise the outer membrane (OM) and periplasmic components [16]. The OM comprises inner and outer phospholipids (PL) and lipopolysaccharide (LPS), combined with interspersed membrane proteins. The lumen of the vesicle may contain a variety of bacterial compounds from the periplasm or cytoplasm, such as proteins, RNA or DNA, and peptidoglycan, which can each act as or encode antigens. The formation of OMVs involves three steps: (1) breakage of connections between OM and peptidoglycan, (2) accumulation of components in the periplasmic space, and (3) activity of specific signal and effector molecules [40]. These processes of OMV formation determine the critical role played by OMVs in the interaction between pathogen and host [41].  
Since the discovery that OMVs can induce an immune response, many studies have aimed to examine the potential for immunization with OMV components. Toxins can act as adhesins for OMVs and therefore allow vesicles to enter cells using the receptor-mediated endocytic pathway [41]. Common components of vesicles, such as outer membrane protein A (OmpA), could also contribute to host cell entry; this adhesin fully activated macrophage cytokine production when presented in the OMV membrane rather than as a mixture of purified vesicle components [41]. OMVs have proper size (20-200 nm), which is an important factor for their efficient processing by APCs, and can present a range of surface antigens in a native conformation, enabling their entry into lymph vessels and uptake by APCs [42]. The natural properties of OMVs, such as their immunogenicity, capacity to act as self-adjuvant, and potential for uptake by immune cells also make them attractive for application as vaccines against pathogenic bacteria [40]. To date, the first generation of OMV vaccines,Bexsero (Novartis) has been approved for the market against serogroup B _Neisseria meningitidis_[43]. Other OMV-based vaccines, though not yet in clinical trial stage, are still being developed in preclinical studies. Additionally, a variety of applications in OMV research and development have been proposed with a focus on infectious diseases (pneumonia, meningitis, and whooping cough) and specifically enteric diseases (cholera, salmonellosis, and shigellosis), most of which utilize OMV antigen binding (Table 1) [44; 45; 46; 47; 48].  
Furthermore, OMVs exhibit a number of functions that aid bacteria in the process of infecting host cells [16]. The most remarkable example is the use of vesicles as a delivery system for pathogen-associated molecular patterns (PAMPs) [49]. OMVs laden with PAMPs, and other OM components that can affect the course of infection and associated host responses are then delivered into distant host cells. The immunogenic properties of OMVs lead to protective mucosal and systemic bactericidal antibody responses that have been exploited for vaccine purposes. Several studies have also documented B-cell responses to OMVs from various bacteria, such as _Escherichia coli_ (_E. coli_), _Salmonella typhimurium_, and _Acinetobacter baumannii_ indicating that OMVs can easily be used as antigen delivery systems to generate effective antibody responses [50; 51; 52; 53]. Indeed, there is a growing interest in the use of OMVs as a delivery system of tumor antigens for the design of cancer vaccines.  
\begin{table}
\begin{tabular}{c c c c c c c c c} \hline \hline
**OMV Source** & \begin{tabular}{c} **Model** \\ **Establishment** \\ \end{tabular} & **Animal Model** & \
\begin{tabular}{c} **Rout of** \\ **Administration** \\ \end{tabular} & **Adjavant Used** & **Protection** &
\begin{tabular}{c} **Resulting Immune** \\ **Response** \\ \end{tabular} & **References** \\ \hline _A. humancelli_ & Sepsis & Female KCR Mice (6-8 weeks \\  & & & & & 73\% survival (compared with 7\% in \\  & & & & & & \\  & & & & & & \\  & & & & & & & \\  & & & & &  
\begin{table}
\begin{tabular}{c c c c c c c c c} \hline