Tackling breast cancer is a monumental task. We began Lumicure cautiously, knowing that there are many risks, ethical concerns, and legal consequences of our project. To address these concerns, we researched potential side effects, the impact of our project beyond the science, and the legal background of cancer treatments. Through constant dialogue with cancer researchers, public health experts, and even everyday people, we gained valuable insight on the policies of Lumicure.
- Cancer treatments have side effects that should be considered when weighing it against other cancer treatments.
- After learning about ethics through the lens of cancer treatment disparities, we emphasized our ability to educate our community.
- We examined the guidelines set by the U.S. Public Health Service and Food and Drug Administration.
Because synthetic biology is a relatively new technology, ethical concerns surrounding the misuse of science and who this technology will benefit inevitably arise. To better understand the impact of our project, we prioritized two ethical issues: risk transparency and cancer treatment disparities.
One of the main concerns is the introduction of genetically modified organisms, specifically E. coli. We should be able to prevent and account for potentially harmful biological material [1]. When introducing modified bacteria, we must consider how organisms will impact patients. When bringing this up Dr. Fischbach, we discussed historically successful cancer therapies, as well as the benefits and drawbacks of each. Specifically, when speaking with Dr. Brooks, we learned how chemotherapy is a powerful but invasive approach, and many patients are reluctant to receive this treatment due to potential side effects. Keeping these safety considerations in mind, we aim to be transparent with our project’s benefits and drawbacks. We also discuss more in our Safety and Risk Assessment.
An ethical issue arises when considering that certain populations receive better cancer treatment than others [2]. Area-level education has explained 31-39% of differences in breast cancer tumor size [3]. Our collaboration with Dr. Amelia Safi to address these disparities has propelled us to think more critically of our work beyond the lab. She pointed out that one of the leading causes of cancer treatment disparities is unequal education. From a young age, underprivileged students are stunted from reaching economic success, ultimately resulting in the vast treatment gap between communities of different upbringings. Since then, we participated in a 4H mentorship program for high school students and guided a student towards higher education in art and science.
Our project is committed to addressing our impact: through the patients that our therapeutic can treat and the mentorship that we can provide along the way.
The United States has passed a variety of laws throughout history regarding cancer research and healthcare. The Triple-Negative Breast Cancer Research and Education Act of 2019 (H.R. 5939) increased funding for triple-negative breast cancer research [1]. The Breast Cancer Research Stamp Reauthorization Act of 2015, P.L. 114-99 (S.1170/H.R. 2191) authorized the US Postal Service to issue a semipostal to raise funds. 70% of these funds went towards breast cancer research at the National Institute of Health from these Breast Cancer Research Stamps [2]. The Breast Cancer Patient Protection Act of 2003 amended the Public Health Service Act & Employee Retirement Income Security Act of 1974. The new requirements included individual and group health insurance coverage as well as a minimum 48 hour hospital stay for mastectomy patients [3]. The Henrietta Lacks Enhancing Cancer Research Act of 2019 (H.R. 1966, S. 946) aims to hold federal agencies accountable for including underrepresented individuals in testing trials[1]. Lumicure wants to ensure that all people who need our bacterial therapeutic have access to it. While this legislation does not directly affect Lumicure, it has impacted our process and will continue to do so as we consider future steps regarding funding and clinical trials.
We realize that with a breast cancer therapeutic we will be one day working with humans. To do so, we must examine the guidelines that the U.S. Public Health Service and Food and Drug Administration set. The FDA sets guidelines to regulate the approval of Microbial Vectors used for Gene Therapy (MVGTs)[4]. To approve our breast cancer therapy MVGT as an Investigational New Drug (IND), our next steps would be:
- Creating a document with descriptions of product manufacturing components and procedures.
- Perform microbial purity testing to demonstrate that the product does not contain unwanted fungal and bacterial organisms.
- Perform sterility testing to showcase that all components do not exceed the chemical and physical limits during clinical investigation.
- Perform stability testing to ensure a stable product during various stages including formulation and injection into a patient.
- Perform antibiotic sensitivity testing and include therapy antibiotics for the bacteria the product is derived from.
- Qualification of the manufacturing process to demonstrate that the product follows guidelines and manufacturing controls in order to progress to Stage 1 clinical trials.
- Begin preclinical trials using animal species and models. Evaluate toxicology and relationship of MVGT to the test subjects.
- Identify potential risks of toxicity in live test subjects and use it to guide a dosage recommendation. Isolate immune responses associated with the MVGT.
- Conduct attenuation evaluation and create a biodistribution/shedding profile for the MVGT.
- Proceed to clinical studies. First, identify general considerations for MVGT procedure. In-vivo survival of MVGT, risk management, and possible infection all need to be addressed.
- Research and discuss previously administered MVGT products and their relevance to the current product.
- Devise a list of eligibility criteria for human clinical trials to isolate a subset of the population that could receive the product with minimal risks.
- Form a dosing schedule and modify based on patient reactions. Monitor patients as they go through different stages of clinical trials.
- These guidelines allow us to manufacture a biological therapeutic that could meet FDA standards for an IND. After completing these steps, we could apply for IND status. Additionally, to manufacture a fluorescent scanner, our next steps would involve:
- Building the fluorescent scanner based on the same specifications as the model used for data gathering and presentation.
- Testing mCardinal to ensure no adverse effects in terms of chemical or physical reactions.
- Evaluate the accuracy and precision of the scanner at identifying fluorescence in the body after mCardinal is administered.
The main concern of our assessment is potential adverse effects on patients. The trichosanthin used in our drug therapy has been utilized in a few research studies [1], but has not been studied extensively in clinical trials, and due to the lack of research, it has not been approved by the FDA. Because of the lack of data available, we cannot be sure that all potential side-effects have been accounted for. To decrease the risks, a kill switch is contained within each plasmid in the bacteria that will destroy the therapeutic if it strays from the target area, or causes adverse effects. Another potential adverse effect is sepsis. In clinical trials for other bacteria therapeutics such as salmonella, the tolerated dose was tested. At high doses there were signs of dangerous inflammation, and with any infection there is the risk of sepsis. To counteract this risk, Lumicure will start out at a low dose and slowly increase in concentration during clinical trials. If signs of inflammation are shown, dose will immediately be lowered and antibiotics will be administered if necessary.
Another crucial part of our project is the fluorescent scanner. Introducing mCardinal into the body, we need to be sure that it will all dissolve or be expelled from the body after it has accomplished its tasks. Lingering and accumulating mCardinal over time could pose a threat to patients. mCardinal is water soluble, so accumulation over time will not be a problem. Regulating the amount of mCardinal within the body is another precaution taken to prevent potential risks. Another consideration with fluorescence is the possible risks of red light [2]. Utilizing low-level light therapy, no harmful tumor growth has been found.
We recommend that Lumicure be taken in conjunction with other breast cancer therapies as it will not completely eradicate breast cancer. Similar to chemotherapy, Lumicure will not destroy all breast cancer tumors, but it will work to minimize the cancer.
Before implementing the bacteria therapy in humans, it is important to meet all FDA regulations. The Quality Risk Management [4] assesses the readiness of a medication or therapy for human use. The FDA published the Quality Risk Assessment to be used as guidance throughout the development process. It examines the risks associated with the product and ensures high product quality. The Quality Risk Assessment begins with identifying a risk. It moves on to analyze and evaluate the risk as shown on the FDA chart below. In the future, our team will conduct a Quality Risk Management Assessment on each concern regarding Lumicure.
[1] SA. Benner, AM. Sismour, et al. “A Priority Paper for the Societal and Ethical Aspects of Synthetic Biology.” Systems and Synthetic Biology, Springer Netherlands, 1 Jan. 1970, link.springer.com/article/10.1007/s11693-009-9034-7.
[2] Anderson, Emily E, and Kent Hoskins. “Individual Breast Cancer Risk Assessment in Underserved Populations: Integrating Empirical Bioethics and Health Disparities Research.” Journal of Health Care for the Poor and Underserved, U.S. National Library of Medicine, Nov. 2012, www.ncbi.nlm.nih.gov/pmc/articles/PMC3826177/.
[3] LA. Carey, CM. Perou, et al. “Disparities in Breast Cancer Prognostic Factors by Race, Insurance Status, and Education.” Cancer Causes & Control, Springer Netherlands, 1 Jan. 1970, link.springer.com/article/10.1007/s10552-010-9572-z.
[1] Cancer Research Legislation. www.cancer.gov/about-nci/legislative/current-congress/cancer-research.
[2] Recent Public Laws. www.cancer.gov/about-nci/legislative/recent-public-laws.
[3] “Important Breast Cancer Legislation.” Amoena, www.amoena.com/us-en/amoena-life/important-breast-cancer-legislation/.
[4] Recommendations for Microbial Vectors used for Gene Therapy Guidance for Industry, September 2016. https://www.fda.gov/media/94200/download
[5] Giga-pixel fluorescent imaging over an ultra-large field-of-view using a flatbed scanner, November 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837097
[1] Byers, V S et al. “A phase I/II study of trichosanthin treatment of HIV disease.” AIDS (London, England) vol. 4,12 (1990): 1189-96. doi:10.1097/00002030-199012000-00002
[2]Myakishev-Rempel, Max et al. “A preliminary study of the safety of red light phototherapy of tissues harboring cancer.” Photomedicine and laser surgery vol. 30,9 (2012): 551-8. doi:10.1089/pho.2011.3186
[3] Gupta, Kapil. “Cancer generated lactic acid: Novel therapeutic approach.” International journal of applied & basic medical research vol. 6,1 (2016): 1-2. doi:10.4103/2229-516X.173976
[4] Guidance for Industry Q9 Quality Risk Management, June 2006. https://www.fda.gov/media/71543/download