Team:Harvard BioDesign/Practices

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Policy and Practices

Our team sought to customize bacterial adhesion for development of targeted microbial therapies for colorectal cancer. We needed to determine the utility of such cancer treatments and what sort of questions would necessarily have to be answered so such technologies may be deployed in people affected by colorectal cancer. We wondered whether there is a need for such need microbial treatments the currently available treatment options. Finally, we questioned if the synthetic biology treatments we envisioned are fundamentally different from small molecule cancer therapeutics, and if this would necessitate engineering specific components to make them suitable for clinical trials. Hence, we consulted with experts in academia and private industry to propose our idea and learn how drug treatments are created, validated, and eventually used to treat patients.

The need for BactoGrip and living cancer therapeutics

We spoke to Dr. Lawrence Shulman, the Deputy Director for Clinical Services at the Center for Global Cancer Medicine, at the University of Pennsylvania. We learned that treatments are more desirable from the perspective of patients and doctors when they are orally administered, toxic only to targeted cells, and affordable. He also stressed that cancer is complex and not defined as a single disease. Rather, biological markers on cancers vary with factors including stage of the disease, necessitating tailor-made treatments for specific cases of cancer. Moreover, invasive surgery is common for treatment of early stage colon cancer. Based on this feedback from Dr. Shulman, we realized that design of our BactoGrip treatment must consider end-user physicians and patients. In this manner, our concept for treatment of colorectal cancer is compelling because of how it could be customized to target specific disease biomarkers by exchaning different cancer binding peptides to the Bactogrip adhesin. Moreover, the therapy meets his criteria for ease of administration to patients since it could be introduced orally and less invasive compared to surgery. Thus, the concept of BactoGrip meets end user criteria for effective cancer therapies and is thus worth pursuing as a project.

Dr. Shulman also suggested that our microbial cancer therapeutic could be especially useful for cancer treatment in developing countries because of the inherent affordability in synthesizing a self replicating, living therapeutic. The exorbitant costs of cancer therapies in the developed world has translated into disparities in cancer treatments compared places of lesser wealth. Such variance is seen even within middle-income countries where there are often higher quality treatments in urban centres compared to less prosperous rural areas. Given this feedback, we realized that the microbial therapeutics we’re proposing are all-the-more desirable they could be produced more cheaply at higher scales compared to small molecule cancer therapeutics. Bactogrip’s customizability and ease of administration could represent a new treatment paradigm which makes cancer therapy more consistent and universally accessible across the globe.

From the lab bench to clinical trials

Dr. Daniel Kronish, the Associate Director of Medical Review at the Harvard Office of Human Research Services (OHRS), informed us about the timelines to bring new cancer therapeutics to market. He told us that the clinical trial process is lengthy and arduous, typically requiring several years for any single drug. Once a potential therapeutic has passed pre-clinical trials in the laboratory, the OHRS must approve clinical trials, review human testing protocols through panels of experts in various disciplines, and ensure that the study design meets rigorous scientific validity standards. This review process ensures criteria including drug dosing are clear and that the study guidelines of those sponsoring the drug are consistent with the care standards set by the OHRS. Dr. Kronish emphasized that our proposed microbial therapeutic would be subject to the same scrutiny as traditional cancer treatments. He made us realize that our microbial treatment might move more slowly through the review process because of inherent differences in its design compared to small molecule therapies.

From this conversation, we desired to learn more about the details of the clinical trial process. We spoke to Dr. Jerome Ritz, the Executive Director at the Connell O'Reilly Cell Manipulation and Gene Transfer Laboratory, in the Dana-Farber Cancer Institute. He emphasized that we should consider in vivo assays in model systems readily adapted to humans in later stage trials to ensure that our work is relevant for when we transition to human subjects. Dr. Ritz also told us about the necessity of setting clear test criteria prior to study of human subjects. He told us to consider which sort of colorectal cancer patients we would enroll in a study because our treatment would only be effective on specific cases of cancer where biomarkers match our customized BactoGrip adhesive protein. We would also have to determine approximate timelines for our therapy to achieve a therapeutic effect so that tumours in patients would be analysed once the microbial anti-cancer agent has had sufficient opportunity to act. Such timelines are critical for recruiting test subjects since individuals would understandably be unwilling to wait for an effect from an experimental therapy and might prefer to seek immediate surgical treatment instead. Through these conversations, we realized that we must begin planning assays well in advance of human trials if we are to ensure such a product is ever to come to market.

Special scrutiny of a microbial cancer therapeutic

To determine the unique scrutiny which our microbial cancer therapeutic might be subjected to and address specific concerns with synthetic biology, we spoke to Dr. Stephen Sonis, a member of the Scientific Advisory Board at ActoGenix. This company is developing genetically engineered bacteria to treat diseases in the gastrointestinal tract and thus Dr. Sonis is particularly knowledgeable on this topic. We mentioned that Dr. Kronish from the Office of Human Research Services suggested that our microbial therapeutic could be difficult to get through regulatory processes because of inherent differences in its design compared to small molecule therapies. Dr. Sonis reported three major safety concerns that ActoGenix faced with development of their own microbial therapies that we have begun using to inform our design.

Firstly, ActoGenix considers public health implications of release of replicating microbial therapeutics into the broader environment. One could envision uncontrolled replication of such an organism causing release of drugs or other cytotoxic agents into waterways. Hence, he suggested that we should devise some method of controlling our bacteria such that it remains viable only in therapeutic environments. Together, we pondered methods for organism containment including active kill switches and engineered auxotrophy. We recognize that such a containment mechanism will be necessary in order to deploy this project as a cancer therapy and must be integrated once we combine BactoGrip adhesive components with cancer-fighting components.

Secondly, Dr. Sonis urged us to consider how whether a microbial therapeutic could have deleterious effects on cancer patients. Before our system could be approved for clinical trials, we would necessarily have to show that our system doesn’t make cancer patients sicker. There are complications which could arise given how a microbial therapeutics might disrupt the balance of the normal human microbiota through competition for resources in the gut. These concerns tie into what we learned about the drug development process from Dr. Kronish and Dr. Ritz. However, studying the balance various species in the overall gut microbiome could necessitate asking different research questions about microflora not typically tested in the development of traditional small molecule cancer therapeutics. Thus, we must devise tests and assays which are relevant to the specific therapeutic mechanism of BactoGrip for preclinical trials.

Finally, Dr. Sonis mentioned that we should consider whether microbial therapeutics could have deleterious consequences in immunocompromised cancer patients. He suggested that pre-clinical trials should explicitly test the therapeutic on immunocompromised mice, considering that cancer patients often have compromised immune systems. To this end, we incorporated his feedback and researched other candidate chassis organisms that would be less immunogenic compared to E. coli K12 from our proof-of-concept assays. We realized that E. coli Nissile has be used as a probiotic and is thus a more desirable chassis for our therapeutic. We transformed our system into this strain and determined that our BactoGrip pili system is compatible with the strain. In future assays, we will continue testing BactoGrip adhesion using E. coli Nissile cells. By incorporating Dr. Sonis’s feedback about immunology of microbial therapeutics in our system, we have taken the first steps to translating BactoGrip from the lab into people.

Ritz Photo

Public acceptance of microbial-based oncological therapies

We asked Dr. Jerome Ritz, the Executive Director at the Connell O'Reilly Cell Manipulation and Gene Transfer Laboratory in the Dana-Farber Cancer Institute, about whether he thought our microbial cancer therapeutic would be welcomed by patients at his practice. He emphasized that while there is understandably public concern over introducing engineered E. coli into the gut microbiome, we can assuage these concerns through showing safety of our product in preclinical and clinical trials, and ultimately showing that microbial therapeutics work. Dr . Ritz said that patients he encounters generally receive experimental treatments positively and are focussed primarily on whether the therapy can help them overcome their disease. We realized that the public is already aware of how controlling their gut microbiome can have positive health impacts with stories in the popular media such as using “poop pills” to restore healthy gut microflora. He told us that our concept therapy is “an innovative approach,” and that we should really strive to continue development of such unique therapeutics. From this conversations, we are confident that our system could achieve widespread public acceptance, but that this is contingent on showing efficacy and addressing other safety concerns around synthetic microorganisms.

Conclusions, experts informing our design, and next steps

From our discussion with experts in academia and private enterprise, we learned that BactoGrip therapeutics are worth pursuing as a cancer treatment. It is desirable since cancer does not specify a single disease and BactoGrip may be customized to treat a broad variety of gut epithelial cancer phenotypes. Moreover, our system is potentially more cost effective because of self-replicating nature of microbial therapeutics and could be used make effective gut anti-cancer therapies more accessible globally. It emerged that BactoGrip therapies would be scrutinized to at least the same extent as traditional small molecule therapeutics. We realized we must incorporate other control mechanisms as design of our system matures to address risks of BactoGrip escaping into non-therapeutic environments. Additionally, we incorporated specific feedback into our design by testing BactoGrip in the probiotic E. coli Nissle to address concerns about microbial therapies in immunocompromised cancer patients. Ultimately, we are using this advice to plan future assays with BactoGrip to ensure widespread acceptance of the therapeutic organism.