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The Listeria strain LmΔactA/ΔplcB with application of two vaccines called ANX-100 and CRS-207 has
been studied [177] . ANX-100 consisted of a vector without antigen that was administered to 9 patients with
colon cancer and hepatic metastasis from colon cancer and demonstrated its safety and tolerability to a
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dose of 1 × 10 CFU. It induced an antitumor inflammatory response. CRS-207 consisted of a modified
strain to express mesothelin, which is an overexpressed antigen that is frequently found in multiple
solid tumors, including mesothelioma, pancreatic adenocarcinoma, non-small cell lung carcinomas and
ovarian cancer [235-237] . Phase I clinical trials in patients with these characteristics showed their efficacy
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and tolerability to a dose of 1 × 10 CFU [177] . Seven patients were treated during these trials. Six patients
had increased survival in 15 months, showing treatment efficacy. But 3 patients with high survival rates
had been treated with GVAX previously. This vaccine was designed to increase GM-CSF expression for
its ability to induce cellular immunity against tumor antigens. Phase II clinical trials were performed
posteriorly [178] . They evaluated the safety and efficacy of the combined treatment with GVAX and
cyclophosphamide (GVAX/Cy) with CRS-207 in contrast to exclusive administration of GVAX/Cy in
patients with pancreatic cancer. Reports showed a global survival rate of 6.1 months in patients treated
with GVAX/Cy+CRS-207, more than patients treated with GVAX/Cy exclusively (HR: 0.59; 95% CI: 0.36-0.97,
P = 0.02).

Based on these results, current research is focusing on efficacy evaluation of vaccines based on Lm
attenuated strains along with other immunological or conventional therapies. Among these, combining
LM-LLO-E7 with anti-PD1 antibodies [238] , or using the strain as adjuvant therapy after chemotherapy
against cervical cancer (NCT02853604). There was also found that combination of CRS-207 strain with
an IDO1 inhibitor increases immunotherapeutic effects in ovarian and peritoneal cancer treatment
(NCT02575807); which could be used as adjuvant therapy after chemotherapy for malignant pleural
mesothelioma (NCT01675765).

Other bacteria under study
Research for bacteria use in cancer treatment is not limited to the cited genres. Lactococcus lactis NK34,
generally used as a probiotic, showed significant antitumor activity against lung, colorectal, gastric
and breast cancers on in vitro models [239] . These effects appear to be mediated by an increase in tumor
expression of p21 and p53 leading to apoptosis [240,241] . Intratumor Streptoccous pyogenes was employed in
pancreatic cancer models and complete tumor regression was observed and associated to cytokine release
and immune cell infiltration [242] . Recently, Bacillus subtilis and Bifidobacterium infantis are being included
in preclinical studies to find more evidence supporting bacteria as life-saving prospects [243-245] .

CONCLUSION
The main advantage of bacterial therapy is its selective colonization in tumor tissue decreasing its
toxicity. This direct oncolytic effect resides on proliferation and immunostimulation that take place in
cancerous tissues. Despite lacking significant effects in initial models and multiple adverse effects, it has
overcome these barriers. Development in genetic engineering has led to better therapeutic effects and
the reinforcement of therapies with molecules such as cytokines, tumor antigens, drug metabolizing
enzymes, death receptors, and even RNA interference. Promising results have been observed with these
therapies during clinical trials. Research is beginning to determine their use as main, or supportive
therapy in contrast to conventional therapy against cancer. Their toxicity, antitumor effect, and their long
half-life represent critical variables to consider in future research protocols and clinical trials. However,
microorganisms versatility remains a feature that may show encouraging results in the future [Table 3] with
significant improvements in cancer diagnosis and treatment.