Senti Bio is perhaps best known for its logic-driven gene circuits used to control the therapeutic activity of cell and gene therapies. But California Biotechnology now has initial data showing its platform has more tricks.
Through the development of CAR-NK cells for solid tumors, Senti has developed a new calibrated delivery technology to fine-tune cytokine signaling to further enhance the function of cell therapy in solid tumors. CAR-NK cells armed with interleukin-15 (IL-15) based on the new gene showed potent antitumor activity and resistance in mice, as well as activation, according to data presented to the American Association for Cancer Research other immune cells.
Senti is already applying the calibrated release technology to several ongoing products, including SENTI-301 and SENTI-401, which are being developed for liver cancer and colorectal cancer, respectively.
Cell therapies are difficult to target in solid tumors because tumors do not contain unique antigens that help immune cells distinguish them from healthy tissue. And the tumor microenvironment can be hostile to the survival of immune cells.
Senti solves the problem of cancer detection with logical genetic circuits that can identify more than one antigen and then activate or block therapy accordingly. To improve the ability of CAR-NK cells, the company is looking for interleukins, taking a common, albeit slightly different, approach to other cell therapy developers, said Tim Lu, MD, in an interview with Senti CEO Fierce Biotech organic Ph.D.D. To research.
“There are two aspects we’re trying to optimize,” said Lu, “one aspect is how we can make NK cells themselves as powerful as possible, and the second is how we use NK cells to regulate the microcirculation of the body surrounding the tumor?”
Once produced, the cytokine is bound to the cell membrane. Senti added a cleavable connector that can be loaded with cell surface protease at Senti projectile velocity, allowing the cytokine to be released in a controlled manner into the surrounding tumor site. In this way, the therapy can achieve optimal stimulation of CAR-NK cells through membrane-bound cytokines and interaction with the local immune community, Lu explained.
Senti chose IL-15 because it’s an established booster for NK cells, Lu said. In the laboratory, CAR-NK cells armed with the novel IL-15 or crIL-15 showed better expansion and survival than those carrying normal IL-15.
In a serial killer assay in which immune cells were regularly regenerated with new cancer cells for 196 hours, crIL-15-CAR-NK cells were able to kill cancer cells at all three-time points, and CAR-NK with IL-15 and NK cells regulated tumor cells only at the starting point.
crib-15 CAR NK cells showed increased durability and antitumor activity in mice, shrinking tumors in 62% of animals, and CAR NK cells alone failed to shrink tumors.
Separately, Senti also showed that the combination of IL-15 and IL-21 has a synergistic effect, as multi-armed NK cells can survive longer in Petri dishes than those armed with IL-15 alone. CAR-NK cells armed with IL-15 and IL-21 killed over 90% of the cancer cells in the lab dishes, and IL-15 alone killed about 70%.
Lu noted that IL-21 is only the first cytokine that Senti presents alongside IL-15. The company is conducting systematic screens to see which cytokines might work with IL-15 in different environments. For example, for SENTI-301, Senti combines IL-15 with IL-12.