A groundbreaking "off-the-shelf" chimeric antigen receptor natural killer (CAR NK) cell therapy has demonstrated remarkable efficacy in patients with relapsed or refractory acute myeloid leukemia (AML), according to interim results from a phase I clinical trial presented at the American Association for Cancer Research (AACR) Annual Meeting 2025.
The investigational therapy, SENTI-202, achieved complete remission in four of seven evaluable patients who had previously failed to respond to or relapsed following standard treatments. All complete responses were ongoing at the time of analysis, with follow-up extending beyond eight months in some cases.
Novel Logic-Gating Technology Addresses AML Treatment Challenges
SENTI-202 represents a significant advancement in cell therapy by employing a sophisticated "logic-gating" approach to overcome the unique challenges of treating AML. According to Dr. Stephen Strickland, Jr., director of leukemia research for Sarah Cannon Research Institute and the study's presenter, AML has proven particularly difficult to target with conventional therapies.
"There is no single target that is uniformly expressed across heterogeneous AML cells, and many targets that are potentially targetable in AML are also expressed on healthy cells," explained Dr. Strickland.
The innovative therapy addresses this challenge through a dual-targeting mechanism that recognizes two different proteins on AML cells—CD33 and FLT3—while incorporating an inhibitory receptor that prevents the CAR NK cells from attacking healthy cells that express EMCN, a protein found on normal hematopoietic stem cells.
"Unlike antibody-drug conjugates or bispecific antibodies, this sort of logic-gating behavior can only be implemented in cell therapies and is a potentially unique way to treat AML by overcoming tumor heterogeneity and sparing healthy cells," Dr. Strickland noted.
Advantages Over Traditional CAR T-Cell Therapy
While CAR T-cell therapy has revolutionized treatment for certain B-cell malignancies, it faces significant limitations in rapidly progressing diseases like AML. Current FDA-approved CAR T-cell therapies require harvesting a patient's own T cells, which are then engineered in a laboratory before being reinfused—a time-consuming process that many AML patients cannot afford.
Additionally, AML patients often have dysfunctional T cells, complicating the manufacturing process. SENTI-202 circumvents these obstacles by utilizing NK cells from healthy donors that can be manufactured in advance and stored until needed, providing a readily available treatment option.
"CAR NK cells can be made from healthy donor cells and stored for future use, making them available as 'off-the-shelf' treatments that can reach patients quickly," Dr. Strickland said. He also noted that CAR NK cells may cause fewer immune-related side effects than CAR T cells.
Promising Efficacy and Safety Profile
The SENTI-202-101 trial enrolled nine patients with relapsed or treatment-refractory AML who received at least one cycle of SENTI-202. Patients underwent lymphodepleting chemotherapy before receiving three to five doses of 1 billion or 1.5 billion CAR NK cells in 28-day cycles.
At the time of analysis, seven patients were evaluable for response. Four achieved complete remission with no evidence of measurable residual disease, and a fifth patient experienced a morphologic leukemia-free state (blast reduction below 5% without platelet and neutrophil count recovery). Three patients subsequently received bone marrow transplants following treatment with SENTI-202.
The therapy demonstrated a favorable safety profile with no dose-limiting toxicities observed. While some patients experienced grade 3 adverse events including febrile neutropenia, decreased platelet count, anemia, and abdominal pain, these were largely attributed to the lymphodepleting chemotherapy rather than the CAR NK cells themselves. No grade 5 adverse events occurred.
Based on these results, the preliminary recommended phase II dose was established as three doses of 1.5 billion cells per cycle.
Implications for Future Cancer Treatment
"The deep and durable responses observed in patients for whom we have follow-up data are impressive," Dr. Strickland remarked. "We are hopeful this can be a new type of treatment for AML patients where the unmet medical need is extremely high."
The researchers believe this approach could potentially extend beyond AML to other cancer types, including solid tumors, where finding cancer-specific targets remains challenging.
"There are very few 'clean' cancer targets that are only expressed on cancer cells but not on healthy cells," Dr. Strickland explained. "The logic-gating technology potentially solves this issue by recognizing one or more cancer targets to trigger deeper cancer killing while recognizing healthy cells to prevent them from being affected."
Ongoing Research
While these early results are promising, the researchers acknowledge limitations including the small sample size, relatively short follow-up period, and lack of direct comparisons to existing treatments. The study continues to enroll additional patients at the preliminary recommended phase II dose to further evaluate SENTI-202's safety and efficacy.
The research is funded by Senti Biosciences, Inc., the developers of SENTI-202, and the California Institute for Regenerative Medicine.
