Bacteria Based Cancer Therapy: A Novel Arena

Cancer is emerging as one of the main causes of mortality worldwide, accounting around 10 million deaths per year and 90% of the overall cancer cases are solid tumors. Therapeutic measures against malignant tumors generally include surgical resection followed by concurrent chemo or radiotherapy. Over the years, various advanced forms of treatment approach have evolved, such as hormone therapy, immunotherapy, gene therapy etc. However, major challenges for current oncotherapeutics include aberrant vascularization, hypoxia, necrosis, abnormally high pH and local immune suppression in the tumor microenvironment. Moreover, adaptive chemo/radio resistance and collateral toxicity eventually lead the tumor cells to invade other organs, a process known as metastasis. These metastatic tumors are the most robust form of cancer. Hence, there is an urgent need to develop some ‘smart’ therapeutic strategies for progressive cancer treatment.

            Years back tumor microenvironment was considered as sterile. It was not until 1813 when anaerobic bacteria Clostridium perfringens was isolated from the tumoral tissue of a cancer patient. Later, it was reported that intratumoral injections with C. perfringens enterotoxin (CPE) in xenografted mouse models showed rapid dose dependent tumor regression. Before 19^th century, bacteria such as Helicobactor pyroli (gastric cancer), Salmonella typhi (hepatobilliary carcinoma) were only believed to be one of the causative agents of cancer. Gradually the concept of using ‘oncolytic’ bacteria for therapeutic applications came into limelight. Oncolytic bacteria are those who have the innate ability to selectively infect, colonize and eradicate malignant tumors. Recently, research works have reported using genetically modified bacteria with lower pathogenicity for anti-tumor therapy.

            The microenvironment within the solid tumors has unique pathophysiology that greatly differs from normal tissue due to abnormal blood vasculature, hypoxia, elevated pH and suppressed immunogenic response. Genetically engineered non-pathogenic variants of anaerobic bacteria such as Salmonella typhimurium VNP20009, Clostridium butyricum M55 are manipulated to specifically grow in such environment. They are used as vectors to selectively express reporter genes, cytotoxic proteins, tumor specific antigens as well as anticancer agents in the tumoral tissues. Hence these bacteria can be utilized both for tumor prognosis as well as therapeutic measures. Some of these bacteria have entered preclinical and clinical trials as tumoricidal agents or suitable candidates for immunotherapy. This Bacteria Based Cancer Therapy (BBCT) still has a vast scope for further research and development that might contribute remarkable insights to the tumor-microenvironment specific customized cancer management.