# Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment
## 4 Challenges in Bacterial Cancer Therapy  
Cancer is a multifactorial disease and the use of bacteria for cancer therapy as an immunostimulatory agent or as a vector for carrying the therapeutic cargo is a promising treatment method. Several clinical trials are underway to test the efficacy of bacterial therapy on human subjects (Table 3). However, a major problem with bacteria mediated cancer therapy is the toxicity. The dose for obtaining therapeutic effect may be toxic and have deleterious effects whereas lower doses can affect the treatment efficacy [15]. The balance between the benefit and safety of the trial subject must be maintained. Appropriate techniques and measures must be adopted to evaluate the immune response of the subject and the overall therapeutic benefit [134]. Differences in tumor structure between preclinical animal models and the human subjects can impact bacterial penetration and proliferation in the tumor [5]. Hence, optimization of the dose and route of administration is critical. Moreover, bacterial clearance by the immune system before reaching the tumor site may result in the failure of treatment [135]. Also, any mutations in the bacteria may result in the therapeutic loss and cause exaggerated infections. However, the use of recombinant DNA technology has mostly solved the safety concerns [15].  
\begin{table}
\begin{tabular}{c c c c c c c} \hline \hline
**Bacterial Strain** & **Gene/Strain** & **Tumor Model** & **Phase** & **Observation** & **Identifier (NCT Number)** & **Reference** \\ \hline \multirow{6}{*}{_Salmonella typhimurium_} & VNP20009 with HSV-TK & B16F10 melanomas & 1 & \begin{tabular}{c} Dose-dependent suppression of tumor \\ growth and prolonged survival \\ \end{tabular} & NCT00004988 & [136] \\ \cline{2-6}  & VNP20009 & Metastatic melanoma, metastatic renal cell carcinoma & 1 & \begin{tabular}{c} Induced a dose-related increase in the \\ circulation of proinflammatory cytokines, \\ such as IL-19, TNF-\(\alpha\), IL-6, and IL-12 \\ \end{tabular} & NCT00006254 & [137] \\ \cline{2-6}  & \(\chi\)4550 with IL-2 & \begin{tabular}{c} Hepatoma, \\ liver neoplasms \\ \end{tabular} & 1 & \begin{tabular}{c} Consistent reduction in the mean number of \\ hepatic metastases in fed animals \\ \end{tabular} & NCT01099631 & [138] \\ \hline \multirow{6}{*}{_Salmonella typhimurium_} & VXM01 & Pancreatic cancer & 1 & \begin{tabular}{c} Reduction in tumor perfusion \\ after vaccination \\ \end{tabular} & NCT01486329 & [139] \\ \cline{2-6}  & JNJ-64041809 & \begin{tabular}{c} CT26 Colon tumor, \\ Prostate cancer \\ \end{tabular} & 1 & \begin{tabular}{c} Breaking of self-tolerance and \\ long-term survival \\ \end{tabular} & NCT02625857 & [140] \\ \cline{2-6}  & GVAX+ CRS-207, \\ \cline{2-6}  & Drug: Cyclophosphamide & Metastatic pancreatic cancer & II & \begin{tabular}{c} Extended survival for patients with \\ pancreatic cancer, with minimal toxicity \\ \end{tabular} & NCT01417000 & [141; 142] \\ \cline{2-6}  & ADXS11-001 & Cervical Cancer & II, III & Promising safety and efficacy results & NCT02853604 & [143; 144] \\ \cline{2-6}  & _nevyi-NT_ & Solid tumor malignancies & 1 & Reduced the tumor size & NCT01924689 & [145] \\ \cline{2-6}  & _nevyi-NT_ & \
\begin{tabular}{c} Refertory advanced \\ solid tumors \\ \end{tabular} & 1 &
\begin{tabular}{c} Ongoing \\ \end{tabular} & NCT03435952 & [146] \\ \hline \hline \end{tabular}
\end{table}
Table 3: Summary of the active clinical studies focused on bacterial mediated anti-cancer therapy [1, 4, 6].