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AACR 2025: Off-the-Shelf CAR NK Therapy SENTI-202 Shows Potential for Complete Remission in R/R AML
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Key Takeaways
- SENTI-202, a CAR NK cell therapy, targets AML cells using logic-gated technology, sparing healthy cells and addressing AML treatment challenges.
- In the phase 1 trial, 4 of 7 evaluable patients achieved complete remission, demonstrating promising efficacy for SENTI-202.
Interim results from the phase 1 SENTI-202-101 trial show that SENTI-202, a logic-gated, off-the-shelf chimeric antigen receptor natural killer (CAR NK) cell therapy, achieved complete remission in 4 patients with relapsed or refractory (R/R) acute myeloid leukemia (AML).
Interim results from the phase 1 SENTI-202-101 clinical trial (NCT06325748) investigating SENTI-202 (Senti Biosciences), a first-in-class off-the-shelf chimeric antigen receptor natural killer (CAR NK) cell therapy, were presented at the 2025 American Association for Cancer Research (AACR) Annual Meeting in Chicago, Illinois. SENTI-202 is equipped with logic-gated technology, which has demonstrated promising early efficacy and a favorable safety profile for relapsed or refractory (R/R) acute myeloid leukemia (AML). Several patients who had previously failed other treatments experienced complete remission, providing promise for a potential treatment option for a patient population with limited therapeutic options available.
“The deep and durable responses observed in patients for whom we have follow-up data are impressive,” said study investigator Stephen Strickland, Jr, MD, MSCI, director of leukemia research for Sarah Cannon Research Institute in Nashville, Tennessee, who presented the data at the AACR Annual Meeting. “We are hopeful this can be a new type of treatment for patients with AML where the unmet medical need is extremely high.”
Leukemia observed in human blood cells under a microscope at 1000x magnification. Image Credit: © ShStock - stock.adobe.com
In recent years, CAR T-cell therapy has revolutionized treatment for certain B-cell malignancies, offering substantial survival benefits in diseases such as multiple myeloma and some types of leukemia and lymphoma. However, this approach has not translated as successfully to AML, due in large part to the disease’s biological complexity.
AML is a heterogeneous malignancy that is characterized by a wide variety of genetic mutations and surface antigens, which makes it challenging to identify a single, uniform target for cell-based therapies. Moreover, many antigens expressed on AML cells are also found on healthy hematopoietic cells, raising the risk of on-target, off-tumor toxicity. Additionally, patients with AML often have compromised immune systems and dysfunctional T cells, which further complicates the manufacturing of autologous CAR T-cell therapies that rely on collecting and engineering the patient's own T cells.
To address these challenges, Strickland and his co-investigators from the Sarah Cannon Research Institute, as well as other collaborating institutions, explored an alternative cellular therapy platform: NK cells. Unlike T cells, NK cells can be derived from healthy donors and used to create allogeneic, “off-the-shelf” therapies that are readily available. This bypasses the time-consuming manufacturing process associated with autologous CAR T-cell therapy. NK cells also carry a lower risk of graft-vs-host disease and may produce fewer severe immune-related adverse effects (AEs).
SENTI-202 builds on the NK cell platform by incorporating a logic-gated design. This gene circuit allows the engineered NK cells to recognize and attack AML cells expressing either of 2 surface antigens—CD33 or FLT3—broadening their effectiveness across a more diverse range of leukemic cells. Importantly, the therapy also includes a built-in safety mechanism: an inhibitory receptor that spares healthy hematopoietic stem and progenitor cells (HSPCs) if they express EMCN, a marker not found on leukemic cells. This logic gating represents a novel synthetic biology approach designed to increase precision and reduce off-tumor toxicity—capabilities unique to cell therapies and unattainable with traditional antibody-based approaches.
“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,” Strickland said in an AACR statement. “There are very few 'clean' cancer targets that are only expressed on cancer cells. The logic-gating technology potentially solves this issue by recognizing 1 or more cancer targets to trigger deeper cancer killing while recognizing healthy cells to prevent them from being affected.”
As of the January 2025 data cut-off, 9 patients with R/R AML had been treated with at least 1 cycle of SENTI-202. Patients received lymphodepleting chemotherapy followed by 3 to 5 doses of CAR NK cells over a 28-day period. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. The preliminary recommended phase 2 dose was determined to be 3 doses of 1.5 billion cells per cycle.
Seven of the 9 patients were evaluable for efficacy at the time of analysis. Of these, 4 achieved complete remission, all without measurable residual disease, and a fifth patient attained a morphologic leukemia-free state. Notably, all complete responses remained ongoing, with some patients reaching over 8 months of follow-up, and 3 of the responders were able to proceed to potentially curative bone marrow transplantation.
The therapy’s safety profile also appears favorable. While some grade 3 or higher AEs were reported—such as febrile neutropenia, thrombocytopenia, anemia, and abdominal pain—most were related to the lymphodepleting chemotherapy and not directly attributed to SENTI-202. No treatment-related deaths or grade 5 AEs occurred. Mild cytokine release syndrome, a common immune-related AE in cell therapy, was reported only as grade 1 to 2 pyrexia in 3 patients.
Further supporting the efficacy of SENTI-202, pharmacokinetic analyses detected the presence of the therapy’s transgene in peripheral blood for up to 15 days post-infusion. CyTOF analysis of bone marrow samples in responding patients revealed a decrease in leukemia stem cells and preservation or even expansion of healthy HSPCs, validating the intended mechanism of action and sparing effect of the logic-gated design.
The SENTI-202-101 trial is ongoing, with additional patients being enrolled at the recommended phase 2 dose to further assess safety, efficacy, and durability of response. Future cohorts will also evaluate a more intensive dosing schedule (schedule 2), which may enhance therapeutic outcomes.
