Equipping living cells with logic gates to fight cancer

One of the most exciting developments in cancer treatment is a wave of new cell therapies that train a patient’s immune system to attack cancer cells. Such therapies have saved the lives of patients with certain aggressive cancers and few other options. Most of these therapies work by teaching immune cells to recognize and attack specific proteins on the surface of cancer cells.Unfortunately, most proteins found on cancer cells aren’t unique to tumors. They’re also often present on healthy cells, making it difficult to target cancer aggressively without triggering dangerous attacks on other tissue. The problem has limited the application of cell therapies to a small subset of cancers.Now Senti Bio is working to create smarter cell therapies using synthetic biology. The company, which was founded by former MIT faculty member and current MIT Research Associate Tim Lu ’03, MEng ’03, PhD ’08 and Professor James Collins, is equipping cells with gene circuits that allow the cells to sense and respond to their environments.Lu, who studied computer science as an undergraduate at MIT, describes Senti’s approach as programming living cells to behave more like computers — responding to specific biological cues with “if/then” logic, just like computer code.“We have innovated a cell therapy that says, ‘Kill anything displaying the cancer target, but spare anything that has this healthy target,’” Lu explains. “Despite the promise of certain cancer targets, problems can arise when they are expressed on healthy cells that we want to protect. Our logic gating technology was designed to recognize and avoid killing those healthy cells, which introduces a whole spectrum of additional cancers that don’t have a single clean target that we can now potentially address. That’s the power of embedding these cells with logic.”The company’s lead drug candidate aims to help patients with acute myeloid leukemia (AML) who have experienced a relapse or are unresponsive to other therapies. The prognosis for such patients is poor, but early data from the company’s first clinical trial showed that two of the first three patients Senti treated experienced complete remission, where subsequent bone marrow tests couldn’t detect a single cancer cell.“It’s essentially one of the best responses you can get in this disease, so we were really excited to see that,” says Lu, who served on MIT’s faculty until leaving to lead Senti in 2022.Senti is expecting to release more patient data at the upcoming American Association for Cancer Research (AACR) meeting at the end of April.“Our groundbreaking work at Senti is showing that one can harness synthetic biology technologies to create programmable, smart medicines for treating patients with cancer,” says Collins, who is currently MIT’s Termeer Professor of Medical Engineering and Science. “This is tremendously exciting and demonstrates how one can utilize synthetic biological circuits, in this case logic gates, to design highly effective, next-generation living therapeutics.”From computer science to cancer careLu was inspired as an undergraduate studying electrical engineering and computer science by the Human Genome Project, an international race to sequence the human genome. Later, he entered the Harvard-MIT Health Sciences and Technology (HST) program, through which he earned a PhD from MIT in electrical and biomedical imaging and an MD from Harvard. During that time, he worked in the lab of his eventual Senti co-founder James Collins, a synthetic biology pioneer.In 2010, Lu joined MIT as an assistant professor with a joint appointment in the departments of Biological Engineering and of Electrical Engineering and Computer Science. Over the course of the next 14 years, Lu led the Synthetic Biology Group at MIT and started several biotech companies, including Engine Biosciences and Tango Therapeutics, which are also developing precision cancer treatments.In 2015, a group of researchers including Lu and MIT Institute Professor Phillip Sharp published research showing they could use gene circuits to get immune cells to selectively respond to tumor cells in their environment.“One of the first things we published focused on the idea of logic gates in living cells,” Lu says. “A computer has ‘and’ gates, ‘or’ gates, and ‘not’ gates that allow it to perform computations, and we started publishing gene circuits that implement logic into living cells. These allow cells to detect signals and then make logical decisions like, ‘Should we switch on or off?’”Around that time, the first cell therapies and cancer immunotherapies began to be approved by the Food and Drug Administration, and the founders saw their technology as a way to take those approaches to the next level. They officially founded Senti Bio in 2016, with Lu taking a sabbatical from MIT to serve as CEO.The company licensed technology from MIT and subsequently advanced the cellular logic gates so they could work with multiple types of engineered immune cells, including T cells and “natural killer” cells. Senti’s cells can respond to specific proteins that exist on the surface of both cancer and healthy cells to increase selectivity.“We can now create a cell therapy where the cell makes a decision as to whether to kill a cancer cell or spare a healthy cell even when those cells are right next to each other,” Lu says. “If you can’t distinguish between cancerous and healthy cells, you get unwanted side effects, or you may not be able to hit the cancer as hard as you’d like. But once you can do that, there’s a lot of ways to maximize your firepower against the cancer cells.”Hope for patientsSenti’s lead clinical trial is focusing on patients with relapsed or refractory blood cancers, including AML.“Obviously the most important thing is getting a good response for patients,” Lu says. “But we’re also doing additional scientific work to confirm that the logic gates are working the way we expect them to in humans. Based on that information, we can then deploy logic gates into additional therapeutic indications such as solid tumors, where you have a lot of the same problems with finding a target.”Another company that has partnered with Senti to use some of Senti’s technology also has an early clinical trial underway in liver cancer. Senti is also partnering with other companies to apply its gene circuit technology in areas like regenerative medicine and neuroscience.“I think this is broader than just cell therapies,” Lu says. “We believe if we can prove this out in AML, it will lead to a fundamentally new way of diagnosing and treating cancer, where we’re able to definitively identify and target cancer cells and spare healthy cells. We hope it will become a whole new class of medicines moving forward.”