Abstract
The tumor microenvironment is characterized by anomalous vascularization, hypoxia, and acidity at the core of solid tumors that culminates in concentrated necrosis and immune system dysregulation among other effects. While this environment presents several challenges for the development of oncotherapeutics that deliver their activity via the enhanced permeability and retention (EPR) effect of the leaky blood vessels around a tumor, oncolytic bacteria, or a class of bacteria with a noted capacity to lyse solid tumors, are attracted to the very environment found at the center of solid tumors that confounds other therapeutics. It is this capacity that allows for a potent, active penetration from the tumor margins into the core, and subsequent colonization to facilitate lysis and immune reactivation. Clostridium novyi in particular has recently shown great promise in preclinical and clinical trials when administered directly to the tumor. These studies indicate that C. novyi is uniquely poised to effectively accomplish the long sought after “holy grail” of oncotherapeutics: selective tumor localization via intravenous delivery. This study reports the development of efficient methods that facilitate experimental work and therapeutic translation of C. novyi including the ability to work with this obligate micro-anaerobe on the benchtop. Additionally, this study seeks to utilize this newfound experimental flexibility to address several gaps in the current knowledge regarding the efficacy of CRIPSR/Cas9-mediated gene insertion in this species to further develop this oncolytic bacteria and the genetic customization of bacteria in general.
Highlights
The microenvironment of a solid tumor is considered a challenge for chemotherapeutic delivery
Recent literature reports have indicated that this local tumor environment may intrinsically promote further tumor development and subsequent metastases (Boedtkjer and Pedersen, 2020). Despite these challenging conditions under which the majority of oncotherapeutics attempt to passively diffuse into the tumor with assistance from the enhanced permeability and retention (EPR) effect (Minchinton and Tannock, 2006), chemotherapeutics have been the standard of care for solid tumors for decades, and shown great efficacy (Miller et al, 2019)
Colony cracking and PCR of the anaerobic bacterial cultures resulted in amplicons of the expected length (Figure 1C), confirming the presence of C. novyi
Summary
The microenvironment of a solid tumor is considered a challenge for chemotherapeutic delivery. Poor vascularization of solid-state tumors is arguably the most difficult aspect of the microenvironment that limits the development of effective therapeutics. The disorganization of the intricate network of blood vessels caused by uncontrolled cellular growth leads to cells abnormally distant from local vessels, limiting oxygen diffusion as well as severely restricting other necessary nutrients (Minchinton and Tannock, 2006; McKeown, 2014)
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