Despite recent improvements in treatment, R/R AML is associated with poor outcomes. Novel well-tolerated therapies that can lead to measurable residual disease negative (MRD-) and durable complete remissions (CR) are urgently needed. SENTI-202 selectively kills AML blasts and leukemic stem cells (LSCs) via its bivalent CD33/FLT3 CAR (OR gate); and spares hematopoietic stem & progenitor cells (HSPCs), even if they express CD33/FLT3, from potential off-tumor on-target toxicity by recognizing the healthy cell antigen EMCN via its unique NOT gate. Here, we report on clinical data from 12 R/R AML patients (pts) enrolled in the completed dose finding cohort used to determine the recommended Phase 2 dose (RP2D). Correlative data from the clinical trial is submitted as a separate abstract.

SENTI-202-101 (NCT06325748), is an ongoing Phase 1 trial, that enrolls adult pts with R/R CD33/FLT3 expressing hematologic malignancies, including AML, who have been treated with 1-3 prior lines of therapy. The study is designed to evaluate 2 Dose Levels (DLs) of SENTI-202 (1x109 & 1.5x109 CAR+ NK cells/dose) and 2 Dose Schedules (Sch) [Days 0, 7, 14 (Sch-I) or Days 0, 3, 7, 10, 14 (Sch-II)] following lymphodepletion (LD) with fludarabine (30 mg/m2/day) and cytarabine (Ara-C) (2 g/m2/day) on Days -7 to -3. The primary objective of the dose finding cohort is safety and determination of maximum tolerated dose (MTD) and/or RP2D; with efficacy being another key objective. Adverse events (AEs) are graded per CTCAE v5 or ASTCT criteria. Efficacy is assessed per European LeukemiaNet 2022 (ELN22) guidelines locally, including MRD, generally with multiparametric flow cytometry (sensitivity of ≤1/10-4) per respective institutional protocols.

As of 15 Jul 2025, 12 R/R AML pts with a median age of 53 years (range 19, 72) were treated at DL1 in both Sch-I and Sch-II (3 pts each) and DL2 in Sch-I (6 pts) with median of 2 (1, 2) cycles of SENTI-202. At baseline, the median time from diagnosis was 10 months (mo) (range 3, 74 mo) & median BM blasts 22% (range 10, 93%). 8 pts were adverse-risk per ELN22. Pts received a median of 2 prior lines (range 1, 3) & 6 pts were primary refractory. All pts received prior chemotherapy including Ara-C and 10 pts received prior venetoclax. SENTI-202 is well tolerated with no dose limiting toxicities and RP2D is confirmed at Sch-I DL2 based on the totality of clinical & correlative data. Grade (G) 3-4 treatment emergent AEs in > 1 pt were platelet count decreased & febrile neutropenia (5 pts each), anemia & abdominal pain (3 pts each), all generally related to LD & unrelated to SENTI-202 except in 1 pt with febrile neutropenia & platelet count decreased. SENTI-202 related AEs of interest (AEIs) in > 1 pt were G1-2 pyrexia reported as cytokine release syndrome (3 pts), which resolved with standard of care (generally within 24 hours). There were no G5 treatment emergent AEs or SENTI-202 related serious AEs. 6 of 12 pts (50%) achieved an overall response [4 MRD- CR, 1 MRD- CR with partial hematologic recovery (CRh), and 1 MRD+ morphologic leukemia-free state (MLFS)], after 1-2 SENTI-202 treatment cycles (overall % composite complete remissions (or cCR) = 42%, ORR = 50%). In the RP2D cohort, 50% (3 of 6 pts) achieved a cCR. 100% of cCR patients were MRD-. Median duration of response was not reached with ongoing durations of 11+, 10+, 7+, 6 and 1.5+ mo in 5 cCR pts (+ indicates ongoing at time of data cut). 4 pts received post protocol hematopoietic stem cell transplant. In general, the observed PK of SENTI-202 was consistent with other CAR NK cell therapies, with modest peripheral expansion over the first two weeks followed by clearance thereafter. Pharmacodynamic bone marrow cell population data were consistent with clinical responses and SENTI-202's mechanism of action, i.e. reduction of blasts and LSCs along with preservation of HSPCs in cCR pts (additional details in separate abstract).Clinical data from the dose finding cohort of SENTI-202 in the ongoing Phase 1 trial reveals an excellent safety profile for SENTI-202 administered after LD, and promising durable CRs (50% at RP2D, 42% overall, all MRD negative with median duration not reached and longest CR of 11+ mo). An expansion cohort enrolling R/R AML pts has been opened at the confirmed RP2D, and we anticipate presenting data from additional patients at the conference.

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2025
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