Team:ETH Zurich/Description

Story of CATE

This is the story about how we developed the idea of CATE. Click on CATE in Action to find out how CATE is designed to treat tumors. To explore the genetic circuit that makes CATE work, visit our Circuit page. Learn how we structured, organized and executed our project by navigating to the Design page.

Introduction

In 2015, cancer claimed the lives of 8.8 million people and still remains the second leading cause of death. The majority of these cases are due to cancers originating from malignant solid tumors - tumors developing in solid tissues such as breast and liver. In 2013, WHO launched the Global Action Plan for the Prevention and Control of Non-Communicable Diseases 2013-2020, aiming at reducing the global mortality due to diseases such as cancer by 25% by 2020. To fulfill this goal, safe and effective treatment options are required. [1]

Figure 1. Facts about cancer.

Current Cancer Treatments

Today, there are several approaches to treating cancer. In general, they can be divided into two main groups: local and systemic treatment options. Local treatment options include surgery and radiation therapy, while systemic options refer to chemotherapy, targeted therapy and immunotherapy. Typically, the patient will receive a combination of different treatments extended over several weeks to months. [2]

Surgery

Surgery is a local treatment modality that includes removal of the visible tumorous tissue along with a margin of healthy tissue of a variable size. [3]

PRO

  • usually a one time procedure
  • well established
  • great for large and isolated solid tumors

CONS

  • locally invasive and damaging
  • can be inadvisable in patients with preexisting conditions (e.g. older patients with cardiovascular diseases might be unable to undergo anesthesia)
  • not available for all sites
  • not suitable for curing a metastatic disease
  • can't guarantee the removal of invisible "micrometastases" in the vicinity of the primary tumor site
  • can be difficult to repeat if initial procedure fails
Radiotherapy

Radiotherapy includes using ionizing radiation to cause lethal mutations in cancer cells. It relies on the fact that normal tissue repairs damage faster and more efficiently than cancerous tissue. [4]

PROS

  • not locally invasive
  • always includes a safety margin to ensure destruction of micrometastatic spreading

CONS

  • conventional treatment regimen takes several weeks to complete
  • normal tissue between the skin and the tumor is always affected
  • long-term mutagenic and carcinogenic effects
  • short-term acute damages
Chemotherapy

Chemotherapy is the treatment of cancer with conventional anti-cancer drugs. These are not specifically targeted, but tend to inflict more damage to rapidly-dividing cells. [5]

PROS

  • systemic treatment that can destroy all cancer cells in the body
  • inexpensive compared to other options

CONS

  • dose and therefore efficiency of killing limited by severe systemic side effects due to lack of targeting
  • usually involves several treatments extended over weeks or months
Targeted Therapy

Targeted therapy involves a group of drugs that are more specific than typical chemotherapeutics. It includes small molecules that target mutations in cancer cells that let them grow, divide and spread. A group of monoclonal antibodies that inhibit growth of cancer by targeting and blocking specific surface receptors that are overexpressed on cancer cells also belong in this type of therapy. On the other hand, monoclonal antibodies that work by labelling the target cells for immune destruction are considered to be a part of Immunotherapy (see below). [6]

PROS

  • in theory, only damaging to the tumor and not the healthy tissue

CONS

  • requires a specific, ideal target and currently, these are unknown for most of the tumors
  • systemic side effects still occuring
Immunotherapy

Immunotherapy is one of the most recent approaches to treating cancer and involves helping the patient's own immune system to fight the tumor through different strategies. CAR-T cells, the most promising form of immunotherapy, involve genetically engineering patient's own immune cells to target individual cancers specifically. [7]

PROS

  • tailored to an individual
  • potentially offering long lasting protection against the cancer
  • autologous (patient-derived) cells and therefore not immunogenic
  • specific for the cancer and can avoid normal tissue

CONS

  • unpredictable systemic side effects seen in clinical trials
  • specific targets/antigens still need to be found for every type of tumor, especially for solid tumors
  • expensive
  • complicated to produce

Some of the therapeutic options mentioned above are well established and have been used for decades, while others represent pioneering treatments developed thanks to advances in biological engineering. However, as seen from the list of pros and cons, no strategy is perfect. Therefore, complete removal of cancer without inflicting damage on the healthy tissue remains a challenge. [8]

Bacteria in Cancer Therapy

To tackle the challenge of treating cancer, we decided to look beyond these more established approaches and from the point of view of a synthetic biologist. Our search led us to the concept of bacterial cancer therapy - a strategy for treating cancer that actually dates back to the beginning of the 20th century but has since changed significantly. In the beginnings, different species of unmodified bacteria were given intravenously to cancer patients and were shown to accumulate preferentially in the tumorous tissue. [9] This attractive inherent feature has been investigated since and is thought to be due to a combination of mechanisms, including:

  • entrapment of bacteria in the chaotic vasculature of the tumor,
  • production of chemotactic agents in the tumor microenvironment and
  • protection from the immune system that the microenvironment, as an immuno-privileged site, offers. [10]

Although native cytotoxicity of the bacteria was shown to inhibit tumor growth to a certain extent, simply administering unchanged bacteria intravenously has been connected to severe side effects and limited efficacy. [11] To overcome this, engineering efforts have been made and different modifications have been implemented and are currently being tested in clinical trials. [12] [13] However, full potential of bacteria as an anti-cancer agent has not yet been fulfilled.

Our vision

In his review on the current state of bacterial cancer therapy [10], Neil Forbes defines an ideal bacterial cancer as:

  • a tiny programmable robot factory that specifically targets tumors,
  • selectively cytotoxic to cancer cells,
  • self-propelled,
  • responsive to external signals,
  • able to sense the local environment and finally,
  • externally detectable.
Figure 2. Features of ideal bacterial cancer therapeutic as implemented into our design. E. coli Nissle 1917 inherently colonizes tumors. Once in this special surrounding, it is designed to recognize the environment (1. Environmental sensing), produce an MRI contrast agent (2. External detectabilty) and accummulate a cytotoxic agent it will later deliver. After confirmation of the correct colonization done by a physician, an external signal is sent via focused ultrasound (3. Response to external signal). This leads to selective delivery of the cytotoxic agent to the tumor (4. Selective cytotoxicity).

CATE, the cancer-targeting E. coli that we have engineered, represents our vision of the ideal bacterial cancer therapeutic. With the combination of autonomous targeting, visualization and externally controlled toxin release, we believe our project provides a novel non-invasive, quick and safe approach to treating cancer (Figure 2).

To learn more about how we envision the actual treatment procedure to look like, see CATE in Action.

For the design of the circuit behind the story, visit to our Circuit page.

References

  1. "Cancer - Fact Sheet" who.int. World Health Organization, Feb. 2017. who.int/mediacentre/factsheets/fs297/en.
  2. "Types of cancer treatment." cancer.gov. National Cancer Institute, Feb. 2017. cancer.gov/about-cancer/treatment/types.
  3. Alim, Eric, et al. "The role of surgery in the treatment of limited disease small cell lung cancer: time to reevaluate." Journal of Thoracic Oncology 3.11 (2008): 1267-1271. doi: 10.1097/JTO.0b013e318189a860
  4. Delaney, Geoff, et al. "The role of radiotherapy in cancer treatment." Cancer 104.6 (2005): 1129-1137. doi: 10.1002/cncr.21324
  5. Romiti, Adriana, et al. "Metronomic chemotherapy for cancer treatment: a decade of clinical studies." Cancer chemotherapy and pharmacology 72.1 (2013): 13-33. doi: 10.1007/s00280-013-2125-x
  6. Wu, Han-Chung, De-Kuan Chang, and Chia-Ting Huang. "Targeted therapy for cancer." J Cancer Mol 2.2 (2006): 57-66. doi: 10.1097/PPO.0000000000000135
  7. Mellman, Ira, George Coukos, and Glenn Dranoff. "Cancer immunotherapy comes of age." Nature 480.7378 (2011): 480-489. doi: 10.1038/nature10673
  8. Miller, Kimberly D., et al. "Cancer treatment and survivorship statistics, 2016." CA: a cancer journal for clinicians 66.4 (2016). doi: 10.3322/caac.21349
  9. Felgner, Sebastian, et al. "Bacteria in cancer therapy: renaissance of an old concept." International journal of microbiology 2016 (2016). doi: 10.1155/2016/8451728
  10. Forbes, Neil S. "Engineering the perfect (bacterial) cancer therapy." Nature reviews. Cancer 10.11 (2010): 785. doi: 10.1038/nrc2934
  11. Patyar, S., et al. "Bacteria in cancer therapy: a novel experimental strategy." Journal of biomedical science 17.1 (2010): 21. doi: 10.1186/1423-0127-17-21
  12. Toso, John F., et al. "Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma." Journal of clinical oncology 20.1 (2002): 142-152. doi: 10.1200/JCO.2002.20.1.142
  13. Brausi, Maurizio, et al. "Side effects of Bacillus Calmette-Guerin (BCG) in the treatment of intermediate-and high-risk Ta, T1 papillary carcinoma of the bladder: results of the EORTC genito-urinary cancers group randomised phase 3 study comparing one-third dose with full dose and 1 year with 3 years of maintenance BCG." European urology 65.1 (2014): 69-76. doi: 10.1016/j.eururo.2013.07.021