Microbial trojan horses: disrupting the tumor microenvironment

Pedro Correa de Sampaio (left) is the CEO and Co-Founder of Neobe (Stevenage, UK), a company engineering microbial trojan horses to carry payloads into solid tumors, which can break down fibrotic barriers in the tumor microenvironment. This approach aims to enable greater drug penetration and immune cell activity within solid tumors, increasing the curative potential of existing therapeutics.

At ELRIG Drug Discovery 2024, Digital Editor Beatrice Bowlby caught up with Pedro to learn more about targeting solid tumors and the potential of Neobe’s synthetic biology platform in developing effective tools for making solid tumors more easily susceptible to cancer therapeutics.

Why are solid tumors so difficult to target using immunotherapies?

The clue is in the name; they’re solid. Solid tumors aren’t clumps of cancer cells floating around. They’re complex tissues gone wrong, with many different components comprising the tumor microenvironment. What we are particularly interested in is the extracellular matrix, which is the fibrotic material that provides the structural integrity of any tissue.

However, in a solid tumor, this matrix is even more heavily cross-linked than in normal tissues, making it very hard to penetrate, even for immune cells. The matrix is so stiff that it causes the vasculature to collapse so you don’t get proper irrigation of the tumor’s components. Additionally, some of these fibrotic components can signal to surrounding immune cells and modify their behavior. This combination of a solid tumor’s physical barriers and the way that it can biochemically affect the behavior of other cells is what makes them so difficult to target with immunotherapies.

Tell us about the synthetic biology platform Neobe is developing and how it can overcome the challenges associated with targeting solid tumors.

To set the scene, I need to tell you that solid tumors are excellent sites for bacteria, which makes sense as the tumor microenvironment is nutrient rich, heavily hypoxic, acidic and free from immune cells. However, in return, bacteria offer the potential to be effective vessels for therapeutic purposes due to their small size, mobility and their desire to live in tumors.

At Neobe, we use synthetic biology to engineer nonpathogenic, commensal strains of bacteria to produce and release an enzymatic payload once they’re within a solid tumor, which breaks down some of the fibrotic components in the tumor’s extracellular matrix. We use strains of bacteria that we know can colonize tumors, and they’re completely safe. By designing and constructing a microscopic trojan horse that can naturally infiltrate tumor sites and break down the extracellular matrix, we are overcoming the physical barrier that blocks drug efficacy in solid tumors.

Ultimately, the problem we’re trying to solve is how to get drugs and immune cells into the tumor effectively. There are a number of therapeutics either commercially available or in advanced development stages that have curative potential, but don’t work in solid tumors because of these barriers to infiltration.  If we can harness our synthetic platform to go into the tumor and basically open the doors for these therapeutics to come in, we think we can unlock this curative potential. We aren’t building a therapeutic ourselves; we’re building a therapeutic enabler.

What techniques have you used to develop this synthetic biology platform?

Much of our work is in genetic engineering. We use molecular biology techniques to build genetic circuits that we can put into our bacteria to program them to do what we want. This requires designing genetic sequences that code for promoters that are active in the tumor, which means that the bacteria are only activated when they sense the physiological and biochemical properties of the tumor microenvironment.

The tumor-induced activation of our synthetic biosensors then triggers the production of an engineered payload. These are enzymes that we selected to precisely modify specific components of the extracellular matrix, reducing its stiffness and increasing tumor irrigation. These payloads are associated with secretion systems to ensure that they are released into the extracellular space of the tumor, targeting the extracellular matrix directly.

To do this, we built extensive genetic libraries, cloned these into bacteria and then tested these prototypes using plate-reading assays, patient-derived tissue samples and animal models. When we test the prototypes, we are trying to see how well the bacteria get into the tumor, how well they break down the extracellular matrix and how well they can get existing commercial therapeutics to work.

How do you see this platform being utilized in future therapeutic scenarios?

We see great potential in what this platform could achieve. We know that there are several therapeutics out there that could work in tumors a lot better and with fewer toxic side effects if we could target them to the tumor microenvironment more effectively and specifically. We are hopeful that eventually we will expand this strategy to work with different therapeutic modalities like antibody–drug conjugates and cell therapies, so we can get these promising therapeutics to work in the highest number of patients possible.

As you’ve started working with animal models, what challenges have you faced?

The main challenge is finding the model that best represents what you see in patients. So far, I’m really excited about the data we’re generating in mouse models. I had the opportunity to present some of our data at ELRIG Drug Discovery, where we’ve shown that we can use our synthetic biology platform to enable full responses in mouse models of breast cancer that previously did not respond to immunotherapies, by sensitizing them with our bacterial products prior to drug delivery. In these models, we see that remodeling the tumor with our synthetic products enables full remission in response to immunotherapy, even when we try to re-introduce the tumor. When you have an animal experiment where you achieve 100% survival, and you have all of these mice that are completely cancer free at the end of the experiment, that is really exciting and encourages us to continue with this work.

What have you most enjoyed at ELRIG Drug Discovery?

I enjoyed the opportunity I had to show some of our mouse model data during my talk. Beyond that, I’ve appreciated the space to connect with the community and see what else is out there. It’s brilliant to meet so many people who are also thinking about new solutions for existing problems that can have a real impact on people’s lives.

The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of BioTechniques or Taylor & Francis Group.