The next frontier of oncotherapy: accomplishing clinical translation of oncolytic bacteria through genetic engineering

The development of a ‘smart’ drug capable of distinguishing tumor from host cells has been sought for centuries, but the microenvironment of solid tumors continues to confound therapeutics. Solid tumors present several challenges for current oncotherapeutics, including aberrant vascularization, hypoxia, necrosis, abnormally high pH and local immune suppression. While traditional chemotherapeutics are limited by such an environment, oncolytic microbes are drawn to it – having an innate ability to selectively infect, colonize and eradicate solid tumors. Development of an oncolytic species would represent a shift in the cancer therapeutic paradigm, with ramifications reaching from the medical into the socio-economic. Modern genetic engineering techniques could be implemented to customize ‘Frankenstein’ bacteria with advantageous characteristics from several species. Side effects of chemotherapeutics are thought to often be a reflection of our inability to target these toxic substances to only cancer cells; hence, scientists have spent centuries searching for alternative treatments that would confine their actions to tumor cells, sparing healthy tissue. Unfortunately, the dense nature of tumor tissue along with altered blood vessels, that lead to diminished tumor tissue oxygenation, altered tissue pH and cellular metabolic inactivity or even cell death have proven challenging. Importantly, these barriers have contributed to local and even sometimes systemic suppression of the patient's immune system that can allow the tumor to grow and progress unchecked. While most non-cancer cells are inhibited by the local tumor environment, certain microbes, including some bacteria and viruses, are drawn to it, possessing a natural ability to selectively infect, colonize and eradicate solid tumors. These microbes may also restore the patient's immune balance. However, use of these microbes is not without its own problems; nevertheless, modern genetic engineering techniques could be implemented to develop customized, safe, effective bacteria with advantageous characteristics. The development and clinical translation of cancer-fighting bacteria would represent a shift in cancer therapeutics and would have ramifications that reach beyond medical efficacy into the realm of socioeconomics. This review seeks to marry the current field of oncolytic bacteria with the expanding field of modern bacterial genetic engineering techniques in prospect of such a therapeutic. Most drugs ar