The Next Frontier of Oncotherapy: Accomplishing Clinical Translation of Oncolytic Bacteria Through Genetic Engineering

Abstract

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.

The Evolution and Future of Targeted Cancer Therapy: From Nanoparticles, Oncolytic Viruses, and Oncolytic Bacteria to the Treatment of Solid Tumors

“…Several oncolytic bacterial species have innate hypoxic sensitivities, especially those that are anaerobic [223,280]. It is worth noting that many of the moieties employed in hypoxia-responsive nanoparticles have the potential to be applied in various forms through genetic modification of oncolytic bacteria to confer added specificity [281]. [234,235,248], OV: [261,262].…”

“…Another adenovirus modification employing the selectivity of acidity as a targeting strategy coated the virus with a pH-sensitive bio-reducible polymer, PPCBA [288], demonstrating feasibility of this mechanism. Again, as with hypoxia, the acidity targeting capacity of oncolytic bacteria is a naturally occurring proclivity of the species in question, but these innate characteristics could be bolstered through further genetic or chemical engineering [281].…”

“…The evaluation of oncolytic viruses is further complicated as animal models frequently lack susceptibility [81]. Moreover, since these oncotherapies function in tandem with the immune system [43,250,251,281], selection of the appropriate pre-clinical murine model is a critical decision for clinical translation. Immune cell populations are altered due to tumors, pre-existing disease states, and previous treatments-which can increase clearance and usually are not replicated in pre-clinical animal modeling [303].…”

“…Only a few select oncolytic bacteria have progressed to clinical trials with only one gaining FDA approval [281,294,378,379]. BCG is an attenuated strain of Mycobacterium with tremendous value as a treatment for non-muscle invasive bladder carcinoma.…”

“…These species share similar features with other oncolytic viruses and bacteria, including pre-clinical genetic engineering, demonstrated antitumor effects in animal models, and natural or artificially enhanced tumor targeting capabilities. However, each of these species displays markedly distinct oncolytic mechanisms [157,201,281,323,366,367,[381][382][383].…”