THERAPEUTIC BACTERIA - NEW CANCER TREATMENT?

By Haya Harris

Abstract

Recent advances in cancer therapeutics have raised the hope for cures for many cancer types. Targeted therapy is a type of cancer treatment that uses drugs or other substances to accurately identify and attack certain types of cancer cells. Another type of cancer therapy is immunotherapy, wherein certain parts of a person's immune system are used to fight such illnesses. However, there are still ongoing challenges in the pursuit of novel therapeutic approaches, including high toxicity to normal tissue and cells, difficulties in treating deep tumor tissue, and the possibility of drug resistance in tumor cells. The use of live tumor-targeting bacteria provides a unique therapeutic option that meets these challenges.

Introduction

The use of therapeutic bacteria is one approach that can overcome some of the limitations of conventional cancer therapy. Bacteria alone can act as potent anti-tumor agents. Another remarkable feature of bacteria is its ability to be genetically engineered. This allows scientists to alter bacteria's ability to synthesize and release specific compounds, and tailor the metabolic pathways. Therapeutic bacteria can especially target the hypoxic (the body or a region of the body is deprived of adequate oxygen supply at the tissue level) areas of tumors. Bacteria can be used as a vector to carry tumoricidal agents and immunotherapeutic agents, thereby destroying tumor cells. However, the fight against cancer is not expected to be won any time soon, so creative efforts to harness the power of bacteria for cancer treatment will continue.

Mechanisms

The fundamental advantage of bacteria-based cancer therapy is the capability to specifically target tumors via unique mechanism1,2. Currently, it is thought that bacteria escape from the blood circulation into tumor tissue via both passive and active mechanisms. Bacteria will initially enter the tumor by passive entrapment in the chaotic tumor vasculature and then, flow into the tumor owing to inflammation. This is caused by a sudden increase in the amount of tumor necrosis factor-α (TNF-α), which is a cell that signals protein involved in systemic inflammation in the tumor vessels3,4. In fact, the active and passive mechanisms are not strain-dependent or mutually exclusive, as bacteria may use both pathways to target tumors specifically.5,6

Motility is a critical feature that enables bacteria to penetrate deeper into tumor tissue7. Unlike the passive distribution and limited penetration intrinsic to chemotherapeutic drugs, bacteria are complex living organisms that can acquire energy from their surrounding environment; thus, their transport capacity is entropically unlimited.8,10 Theoretically, following systemic administration, bacteria can use their self-propulsion abilities to actively swim away from the vasculature and disperse themselves throughout tumor tissue.

Bacterial overgrowth in tumors induces tumor regression via several different mechanisms.

After systemic administration, bacteria localize to the tumor microenvironment9,11. The interactions between bacteria, cancer cells, and the surrounding microenvironment cause various alterations in tumor-infiltrating immune cells, cytokines, and chemokines, which further facilitate tumor regression12,13.

In summary, it is speculated that in addition to its intrinsic antitumor effects, bacterial infection makes its most critical contribution to tumor regression by activating a complex immune cell population in TMEs. Although the primary mechanism varies, it is clear that bacteria likely offer a unique immunotherapy strategy that can be potentiated through sophisticated genetic engineering of bacterial strains.

Conclusions and future perspectives

Tumor-targeting bacteria possess unique features, including tumor selectivity and unlimited gene packaging capability, that make them ideal vehicles for delivering therapeutic payloads in a cancer-specific manner. This unlimited gene packaging capability not only allows the expression of large or multiple target genes, but also supports engineering signaling networks that enables bacteria to perform sophisticated tasks in cancer treatment. Despite the great therapeutic potential of engineered tumor-targeting bacteria, successful cancer therapy will likely require combinatorial approaches, making it very difficult to achieve a cure with single anticancer agents. In addition to chemotherapy and radiotherapy, whose anticancer effects can be synergistic with those of bacteria, intratumoral bacterial infection is attractive as an amendment to other immunotherapeutic approaches.

References

1. McCarthy, E. F. The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas. IOWA Orthop. J. (2006).

2. Clairmont, C. et al. Biodistribution and genetic stability of the novel antitumor agent VNP20009, a genetically modified strain of Salmonella typhimurium. J. Infect. Dis. 1996–2002 (2000).

3. Bhatt AP, Redinbo MR, Bultman SJ. The role of the microbiome in cancer development and therapy. CA Cancer J Clin. 2017.

4. Min, J. J. et al. Noninvasive real-time imaging of tumors and metastases using tumor-targeting light-emitting Escherichia coli. Mol. Imaging Biol. (2008).

5. Mengesha A, Dubois L, Chiu RK, et al. Potential and limitations of bacterial‐mediated cancer therapy. Front Biosci. 2007.

6. Nemunaitis J, Cunningham C, Senzer N, et al. Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients. Cancer Gene Ther.