With the therapeutic potential of engineered cells, we may be closer than ever to curing diseases like type 1 diabetesWith over 1 million Americans living with Type 1 diabetes (T1D), it’s likely that you know someone -- a family member, a friend, a coworker -- suffering from this condition. T1D is not to be confused with Type 2 diabetes (T2D), which results from a complex combination of genetics and lifestyle factors. Unlike T2D, T1D cannot be reversed through diet and exercise programs. Those with T1D have it for life, and depend on insulin injections to survive. Yet the cost of insulin is rising, and 25% of Americans have rationed their insulin supplies due to cost -- a potentially life-threatening decision that many are forced to make.What if there were an economical therapy that could eliminate the need for insulin? What if this therapy could cure T1D -- a goal that we’ve continued to fall short of? Too good to be true?Perhaps not. With living medicines, we may finally be on the cusp of curing T1D.

Redefining drugs: using living cells as therapies

Living medicines are therapies based on cells -- either a person’s own cells or microbial cells -- that have been engineered to deliver therapeutic payloads. These payloads may be FDA-approved drugs or naturally occurring proteins or antibodies. CAR T cells for treating blood cancers are one of the most familiar examples of living medicines.But cancer isn’t the only group of diseases that can be targeted with living medicines. Living medicines can also be designed to treat autoimmune conditions like T1D. Belgium-based ActoBio Therapeutics™ (a wholly-owned subsidiary of Intrexon Corporation) has been developing microbe-based therapeutics for a range of autoimmune and inflammatory conditions since 2006 -- and with two therapeutics in clinical stage (one in phase 2b and one in phase 1b/2a), they are well on their way toward changing the face of healthcare for millions of people. The secret to their success is a microbe that humans have been consuming for millennia.

Cheese microbe-turned therapeutic

Lactococcus lactis is a bacterial species isolated from the dairy environment or plant material. You may not have heard of it, but you have certainly eaten the fruits of its labor: cheese (it is also present in other types of fermented foods, such as pickles and sauerkraut). It doesn’t make you sick when you eat it, and because it isn’t a normal part of the human microbiome (the collection of microbes inhabiting the human body) it doesn’t colonize the human body. In essence, it is an excellent candidate to use as a safe living medicine.The team at ActoBio have engineered a L. lactis platform, called ActoBiotics®, for local delivery to various mucosal sites, including the oral and nasal cavities, the GI tract, and, possibly, skin. Local delivery also gives the therapeutic L. lactis an advantage -- there are no side effects associated with widespread dissemination throughout the body. And, unlike injectable biotherapeutics, there is no purification step necessary -- the patient simply swallows a pill full of engineered bacteria ready to deliver their therapeutic payload -- potentially reducing overall manufacturing costs as well as making the treatment overall much easier to swallow (pun intended).

Image source: ActoBioTherapeutics™So, how does it all work?“We have a capsule formulation that is designed to release its cargo at a distal site of the small intestine -- a neutral pH. The freeze-dried engineered bacteria becomes rehydrated and the bacteria are immediately metabolically active and start secreting the therapeutic agent while moving through the GI tube,” explains Pieter Rottiers, CEO of ActoBio Therapeutics™. Critically, he adds, “this means that the exposure time is determined by the transit time -- in an individual with a normal transit time, the exposure time is between 48 hours and 72 hours.”And, once the bacteria pass through the GI tract and out of the human body, a built-in suicide system kills the microbes, preventing the genetically modified organisms from entering the environment.Such a formulation has obvious utility in GI conditions such as inflammatory bowel disease or even diarrhea. But the ActoBio team has developed a microbe that can be tweaked and tuned to target a number of conditions, from oral mucositis to celiac disease. At the crux of their approach is one characteristic that makes them truly stand out: the ability of their engineered microbe to secrete multiple biologicals targeting multiple disease pathways at once, acting as a combination therapy in one single capsule or topical solution.

Synergy, not silver bullets

The capacity to address multiple targets is viewed by many as critical for successful cell therapies. For example, current CAR T therapies suffer from off target effects due to the presence of the target antigen on healthy and cancerous cells alike. Developing therapies that can recognize multiple targets will make them more precise and potentially more efficacious -- and eventually, personalized. They may even be able to cure diseases. ActoBio’s first candidate for cure is T1D.“We have designed to deliver active ingredients that induce antigen-specific immune tolerance, so that we can block disease progression,” explains Rottiers. “We do this by delivering two specific active ingredients: the antigen, to induce antigen-specific immune tolerance, cytokine IL-10 to enhance tolerance induction. This specific combination is magic -- you need both to have a sufficient induction of antigen-specific immune tolerance.”This therapeutic, called AG019, reversed new-onset T1D in 10-15% of the mice in which it was tested. That percentage was increased to 89% when combined with a short course of systemic immunosuppressive antibody -- a truly astounding number. Even more impressive: normal blood sugar levels remained stable for at least 15 weeks post-treatment without disease recurrence, indicating disease-modifying potential.Of course, it remains to be seen whether the same level of success will be seen in humans, and ActoBio’s T1D L. lactis therapeutic is now in phase 1B/2A clinical trials. The hope is that the treatment will protect the patients’ surviving beta cells (usually around 20-30% at the time of diagnosis), rendering insulin injections unnecessary and effectively curing the disease. Rottiers expects results from the clinical trial to come in by the first half of 2020.

Image source: ActoBioTherapeutics™T1D is only the beginning, says Rottiers. If T1D efforts prove successful, the platform could also be used for other autoimmune conditions like multiple sclerosis, uveitis, and arthritis. And, it could be developed for allergy desensitization -- ActoBio has announced a proof of concept to use their L. lactis to target specific food allergens. They also have a second therapeutic in phase 2b clinical trials for treating oral mucositis, a common complication of cancer treatment.

Working with, not against, regulatory organizations

Rottiers credits much of this progress to working with regulatory organizations right from the beginning.“We approached both the European and US authorities in 2007 with a product based on genetically modified bacteria to be used for human therapy, was completely new to them. We had many discussions with them, and it was a great journey. We learned a lot from each other, and jointly developed the guidelines,” says Rottiers.It also helps that they are using an organism that is safe for human consumption and that poses no contamination threat to the environment.Rather than a bottleneck in the process, Rottiers views ActoBio’s relationship with regulatory authorities as key to helping them move forward. And in his eyes, a future where living medicines are a major component of healthcare isn’t far away.“What we're doing with our products and our strategy is building on that wave,” says Rottiers. “With the demonstrated safety profile and broad applicability of ActoBiotics®, I’m confident that this therapeutic approach will become a pivotal technique for designing and creating the disease-modifying treatments of the future.”Pieter Rottiers will be speaking at SynBioBeta 2019 October 1-3 in San Francisco, CA. Engineered Cell Therapies and Biopharma and Health are two key themes of the conference where you can learn more about the work of companies like ActoBio Therapeutics™.