The diagram above represents the process of chimeric antigen receptor T-cell therapy (CAR). The final result should be a production of equipped T-cells that can recognize and fight the infected cancer cells in the body. Source: Wikimedia Commons
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Living medicines: Accessing the cancer-fighting power within your body

This story is brought to you by Ginkgo Bioworks, a company developing new organisms that replace technology with biology, and Twist Bioscience, a company making DNA for medicine, agriculture, industrial chemicals and data storage.

Chemotherapy is the stone age of cancer treatment. And in far too many cases, it is the very best option doctors and patients have.

It involves administering toxic drugs that kill quickly dividing cells (like cancer cells). Or in the case of more selective drugs, it blocks cellular signals that cause cells to divide. Chemotherapeutic agents go into the bloodstream so they can reach cancer at any location in the body. For these reasons, it has a wide and somewhat indiscriminate impact on the fast-dividing cells of the body, such as blood cells and the cells of the mouth, stomach, and intestines. Whether or not chemotherapy ultimately treats the cancer, its side effects are often felt within hours or days of treatment, and may last from weeks to years with devastating effect.

But now, using tools like synthetic biology, we are more than ever able to use the power to heal that lies within the cells of our very own bodies. Several research groups are studying the use of synthetic biology techniques to treat cancer, the world’s second leading killer, behind cardiovascular disease.

Chimeric antigen receptor T-cell (CAR-T) therapy is a promising new immunotherapy for treating blood cancers like lymphoma or acute lymphoblastic leukemia (ALL) by leveraging a person’s own immune system. A patient’s T-cells are removed from their blood and taken to the lab. There, the cells are exposed to a virus that adds a gene encoding a receptor for the B-cell antigen CD19 to the T-cells. Then, the modified T-cells are infused back into the patient where they target and attack cells with CD19 on their surface.

In clinical speech, this treatment is called adoptive cell therapy. In plain speech, living medicine.

It all sounds exciting, and it is easy to assume that with immunotherapies such as CAR-T we are moving out of the chemotherapy stone age. Dr. Wendell Lim, who has been designing bioengineered cells in his UCSF laboratory for over 5 years, cedes that while the therapy is promising and has an 80% success rate in current applications, CAR-T therapy still has a long way to go.

Wendell Lim
“As we better understand the design rules of cellular networks, we have become interested in applying this knowledge to engineer designer cells that carry out therapeutic functions, such as sensing and destroying cancer.” – Wendell Lim, Principal Investigator at UCSF.

“It is not as safe as getting on an airplane,” says Lim, who entered the synthetic biology world due to his long-held interest in cellular circuits and how responses evolve and can be engineered. Specifically, the process adds only a single antigen receptor specific only to B cells. Because non-cancerous B cells also contain the receptor, normal B cells are rendered collateral damage to the attack on cancer. In the most severe cases, the therapy can cause a serious hyperimmune response in recipients, characterized by a massive cytokine flux in response to dead and dying cancer cells targeted by the modified T-cells.

A major challenge of cancer immunotherapies like CAR-T is that microenvironment around many cancers is immunosuppressive — a trick used by cancerous cells to protect themselves against the immune system. The fact that the T-cell has only a single receptor for B-cells renders them useless for any solid cancers. The engineered T-cells need to be active even in this unconducive environment — and would likely be more effective in the absence of this roadblock.

Dr. Lim believes that further modification of the T cells can help address these risks and challenges. First, T-cells could be engineered to recognize more than one antigen, making them more specific (and potentially useful for non-B cell cancers). He also envisions using engineered cells to control the tumor microenvironment and remodel it, reducing its immunosuppressive properties. He is working toward solutions to both of these problems in his own laboratory, where he also engineers human immune cells to recognize and attack human cells infected with viruses or bacteria.

The microbiome is yet another mechanism by which we may be able to fight cancer. Several studies have shown that bacteria normally residing in the human intestinal tract can affect how effective a chemotherapeutic or immunotherapeutic treatment is, or even modulate drug toxicity. Could we harness the power of our microbial cells — which outnumber our own — to fight cancer? Dr. Lim cautions against viewing the gut microbiome as the silver bullet in cancer therapy. He says that while the gut is easy to modulate, it’s a bit like taking the long, scenic route and believes that directly targeting cancerous cells with engineered cells makes more sense. But for some cancers, he says, directly targeting tumors by engineered host immune cells while concurrently modulating the immune system through the gut microbiome could be an interesting approach.

Synlogic, a Cambridge-based biotech company built primarily on technology from the laboratories of Jim Collins and Tim Lu from Massachusetts Institute of Technology, is well on its way to helping create such an approach. The company has the technology to bioengineer bacteria — specifically, Escherichia coli – as cancer therapeutics. CSO Paul Miller says that they have considered using bioengineered E. coli to modulate the immune system in the tumor microenvironment, and they are looking at factors to enhance or suppress the immune system. “We have been able to produce [secreted molecules] that operate in either direction,” he says.

Synlogic
“The natural power of Synlogic’s approach comes from our engineering of therapeutic metabolic pathways into probiotic bacteria by using our team’s synthetic biology tools and know-how. We capitalize on the bacteria’s naturally-occurring mechanisms for environmental sensing, metabolic conversions, and energy utilization. The end result is living therapeutics, embodied in our synthetic biotics for treating many diseases.”—Paul Miller, Chief Scientific Officer at Synlogic.

Referencing an important drawback to current CAR-T approaches — the inability to use them for solid tumors such as colorectal and pancreatic tumors — Synlogic’s interim president and CEO Aoife Brennan says such cancers are “large opportunities for bacterial-based treatments. [Engineered] bacteria can remain and execute their function for up to two weeks. They can set up long term memory and spread to uninjected tumors as well.”

Synlogic’s bioengineering technology relies on bacterial metabolism, which is versatile and easily modified genetically, especially in E. coli. Targeting bacterial metabolism is an especially promising approach because bacteria, which can be thought of as microscopic bioreactors, don’t care where their substrate comes from — they’ll eat it anyway. Take, for example, IDO inhibitors (also known as checkpoint inhibitors), which inhibit the production of kyurenenin — a metabolite that helps cancer cells evade the immune system. IDO inhibitors have mixed results, likely due to differences in kyurenin upstream targets. Bacteria, on the other hand, simply “eat” kynurenine, no matter which enzyme(s) helped make it.

As with CAR-T therapy, bioengineered bacteria face their own set of challenges. While they are adept at producing small molecules and amino acids, they sometimes struggle with foreign protein production and secretion. And, bacteria interact with thousands of other bacterial, as well as human, cells in the human body. A bioengineered bacterial cell’s function may be completely different in the petri dish than in a living, breathing human full of other microbial cells and metabolites. Brennan reminds us that, “Bacteria are ‘living medicines.’ So metabolic activity will change depending on carbon availability.”

But cancer therapeutics is not Synlogic’s major focus. The accumulation of toxic levels of metabolites lies at the heart of many human diseases and disorders; targeting these toxic build-ups with engineered bacteria could target diseases at their core. Synlogic has developed their technology to be widely applicable, and the company’s patent lists over 100 diseases and disorders that could be targeted by their “engineered probiotics” in the future.  They have partnered with Ginkgo Bioworks — combining their own drug producing ability with Ginkgo’s platform technology — to rapidly investigate a wide variety of approaches. Most studies to date have been done in rodent models, but current phase I trials are ongoing in patients with phenylketonuria (PKU).

PKU
A doctor tests a baby for phenylketonuria (PKU), a rare inherited disorder that causes the buildup of phenylalanine in the body. Untreated, PKU can cause seizures, brain damage, and intellectual disabilities. Source: Wikipedia

Living medicines are poised to change how we treat myriad diseases, not just cancer. With the advent of synthetic biology, we are now able to take systems that have existed within our own bodies since the beginning of time and modify them, turning them into fine-tuned, optimized, disease fighting machines.

Just a few decades ago, scientific advancements such as CRISPR would have sounded akin to science fiction. But the reality is that technologies are growing at such a pace these futuristic ideas could be reality sooner than we think. Science fiction is becoming not only a reality, but an integral part of the future of medicine.

Don’t miss the Focus session: Engineered cancer immunotherapies (sponsored by Distributed Bio) at SynBioBeta 2018, October 3rd, in San Francisco.

This story is brought to you by Ginkgo Bioworks, a company developing new organisms that replace technology with biology, and Twist Bioscience, a company making DNA for medicine, agriculture, industrial chemicals and data storage.

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Embriette Hyde

Embriette Hyde

A trained microbiologist with over 7 years of experience in microbiome research, Dr. Embriette Hyde is passionate about bringing science to the public. She is currently working as Managing Editor at SynBioBeta and mentors K-12 students through Schmahl Science Workshops, fostering passion for science from a young age.

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