The U.S. Food and Drug Administration (FDA) approved the first chimeric antigen receptor (CAR) T-cell therapy in 2017 to treat children with acute lymphoblastic leukemia.¹ Over the past decade, other CAR T-cell therapies have been FDA approved to treat adults with blood cancers, including non-Hodgkin lymphoma and multiple myeloma. However, some blood cancers, including acute myeloid leukemia (AML), present a challenge for cell-based therapies.

Stephen A. Strickland, Jr, MD, MSCI

The results of a small phase I study of SENTI-202, a first-in-class CARnatural killer (NK) cell therapy, showed it was effective in eliciting a complete remission in several patients with AML who had not responded to or relapsed after prior treatments. All complete responses were ongoing, with a maximum follow-up of more than 8 months, and three patients received a bone marrow transplant after treatment with SENTI-202.²The study, conducted by Stephen A. Strickland, Jr, MD, MSCI, Director of Leukemia Research at Sarah Cannon Research Institute, Nashville, and colleagues, was presented during the 2025 American Association for Cancer Research (AACR) Annual Meeting.

Study Methodology and Results

In this phase I SENTI-202-101 clinical trial, the researchers enrolled nine patients with relapsed or refractory AML. As of the data cutoff, the patients had received at least one cycle of SENTI-202. The patients underwent lymphodepleting chemotherapy before being infused with three to five doses of 1 billion of 1.5 billon CAR NK cells given in 28-day cycles. According to the investigators, no dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. The preliminary recommended phase II dose was established as three doses of 1.5 billion cells per cycle.

At the time of analysis, seven of nine patients were evaluable for best overall response, with the remaining two patients continuing on treatment after experiencing disease reduction after completing the first treatment cycle. Four of the seven patients experienced a complete remission, all with no evidence of measurable residual disease (three with full and one with partial hematologic recovery), and a fifth patient experienced a morphologic leukemia-free state (blast reduction below 5% without platelet and neutrophil count recovery).

Safety

Interim clinical data from the ongoing phase I study shows a well-tolerated safety profile for SENTI-202 administered after lymphodepletion. Four patients reported grade 3 or higher febrile neutropenia and a decreased platelet count, and two patients reported grade 3 anemia and abdominal pain, but these side effects were deemed unrelated to SENTI-202 or resulting from the lymphodepleting chemotherapy in all patients except for one. No grade 5 adverse events were observed.

Limitations of the study include its small sample size, short follow-up, and lack of direct comparison to existing treatments. The study is continuing to enroll additional patients at the preliminary recommended phase II dose to further evaluate the safety and efficacy of SENTI-202.

Clinical Significance

“The deep and durable responses observed in patients for whom we have follow-up data are impressive,” said Dr. Strickland, first author of this study, in a statement. “We are hopeful this can be a new type of treatment for AML patients where the unmet medical need is extremely high.… There are very few ‘clean’ cancer targets that are only expressed on cancer cells but not on healthy cells. 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.” 

Disclosure: Funding for this study was provided by Senti Biosciences, the maker of SENTI-202, and the California Institute for Regenerative Medicine. Dr. Strickland reported no conflicts of interest.

References

1. National Cancer Institute: CAR T cells: Engineering patients’ immune cells to treat their cancers. Available at www.cancer.gov/about-cancer/treatment/research/car-t-cells. Accessed April 28, 2025.

2. Strickland SA, Eghtedar A, Farhadfar N, et al: First-in-human, multicenter study of SENTI-202, a CD33/FLT3 selective off-the-shelf logic-gated CAR NK cell therapy in hematologic malignancies, including AML: Clinical data. 2025 AACR Annual Meeting. Abstract CT014. Presented April 27, 2025.