Among the most thrilling advancements in cancer therapies is a surge of innovative cell treatments that educate a patient’s immune system to combat cancer cells. These therapies have rescued the lives of individuals facing certain aggressive forms of cancer with few alternative treatments available. The majority of these therapies function by training immune cells to identify and attack specific proteins situated on the exterior of cancer cells.
Regrettably, many proteins located on cancer cells are not exclusive to tumors. They are also frequently found on healthy cells, complicating efforts to aggressively target cancer without instigating perilous assaults on other tissues. This challenge has restricted the utilization of cell therapies to a narrow group of cancers.
Currently, Senti Bio is endeavoring to develop more intelligent cell therapies by employing synthetic biology. The organization, founded by former MIT faculty member and current MIT Research Associate Tim Lu ’03, MEng ’03, PhD ’08 alongside Professor James Collins, is enhancing cells with gene circuits that enable them to perceive and react to their surroundings.
Lu, who majored in computer science as an undergraduate at MIT, compares Senti’s methodology to programming living cells to function more like computational systems — reacting to particular biological signals using “if/then” logic, akin to computer programming.
“We have pioneered a cell therapy that instructs, ‘Eliminate anything exhibiting the cancer target, but protect anything displaying this healthy target,’” Lu clarifies. “Even though certain cancer targets hold promise, issues may arise when they are present on healthy cells we aim to safeguard. Our logic gating technology was created to identify and avoid harming those healthy cells, which opens up a broad array of additional cancers that lack a single clear target we can now potentially tackle. That illustrates the power of embedding these cells with logic.”
The company’s primary drug candidate is intended to assist individuals with acute myeloid leukemia (AML) who have had a recurrence or show no response to alternative therapies. The outlook for such individuals is bleak, yet preliminary results from the company’s initial clinical trial demonstrated that two out of the first three patients Senti treated achieved complete remission, wherein follow-up bone marrow analyses couldn’t find a single cancer cell.
“It’s essentially one of the best responses you can attain in this disease, so we were genuinely thrilled to observe that,” remarks Lu, who was part of MIT’s faculty until he left to lead Senti in 2022.
Senti anticipates unveiling more patient data during the forthcoming American Association for Cancer Research (AACR) conference at the close of April.
“Our innovative work at Senti illustrates that one can leverage synthetic biology technologies to develop programmable, intelligent treatments for patients battling cancer,” states Collins, who currently holds the position of MIT’s Termeer Professor of Medical Engineering and Science. “This is incredibly exhilarating and showcases how we can apply synthetic biological circuits, specifically logic gates, to craft highly effective, next-generation living therapeutics.”
Transitioning from computer science to oncology
Lu was inspired during his undergraduate studies in electrical engineering and computer science by the Human Genome Project, an international effort to sequence the human genome. Subsequently, he pursued the Harvard-MIT Health Sciences and Technology (HST) program, where he obtained a PhD from MIT in electrical and biomedical imaging and an MD from Harvard. During that period, he worked in the laboratory of his future co-founder at Senti, James Collins, a forerunner in synthetic biology.
In 2010, Lu became an assistant professor at MIT with a combined appointment in the departments of Biological Engineering and Electrical Engineering and Computer Science. Throughout the succeeding 14 years, Lu directed the Synthetic Biology Group at MIT and launched several biotech firms, including Engine Biosciences and Tango Therapeutics, which are also working on precision cancer treatments.
In 2015, a collective of researchers including Lu and MIT Institute Professor Phillip Sharp published findings demonstrating that they could employ gene circuits to compel immune cells to selectively respond to tumor cells within their vicinity.
“One of the initial works we published centered around the concept of logic gates operating within living cells,” Lu mentions. “A computer utilizes ‘and’ gates, ‘or’ gates, and ‘not’ gates, which allow it to execute computations, and we began to publish on gene circuits that implement logic within living cells. These circuits enable cells to detect signals and make logical determinations like, ‘Should we activate or deactivate?’”
During that period, the first cell therapies and cancer immunotherapies began receiving approval from the Food and Drug Administration, and the founders viewed their technology as a means to elevate these methodologies to a higher standard. They officially established Senti Bio in 2016, with Lu taking a sabbatical from MIT to assume the role of CEO.
The company acquired technology from MIT and further advanced the cellular logic gates, allowing them to function with various types of engineered immune cells, including T cells and “natural killer” cells. Senti’s cells can react to specific proteins that are present on the surfaces of both cancerous and healthy cells, enhancing specificity.
“We can now engineer a cell therapy where the cell decides whether to eliminate a cancer cell or preserve a healthy cell, even when those cells are immediately adjacent to one another,” Lu states. “If it’s impossible to tell apart cancerous and healthy cells, you risk undesirable side effects, or you might not be able to attack the cancer as forcefully as desired. But once that distinction is made, there are numerous strategies to maximize your impact against the cancer cells.”
Promise for patients
Senti’s primary clinical trial is concentrating on patients with relapsed or refractory blood cancers, including AML.
“Clearly, the most crucial aspect is achieving positive responses for patients,” Lu remarks. “However, we’re also conducting supplementary scientific investigations to confirm that the logic gates are functioning as anticipated in humans. With that knowledge, we can then implement logic gates into further therapeutic applications such as solid tumors, where similar challenges with identifying a target exist.”
Another company that has collaborated with Senti to incorporate some of Senti’s technology is currently engaged in an early clinical trial for liver cancer. Senti is also forming partnerships with additional companies to utilize its gene circuit technology in fields such as regenerative medicine and neuroscience.
“I believe this extends beyond mere cell therapies,” Lu asserts. “We are confident that if we can validate this in AML, it will pave the way for a fundamentally novel approach to diagnosing and treating cancer, wherein we can definitively identify and target cancer cells while sparing healthy cells. We aspire for it to evolve into an entirely new category of medicines going forward.”