Senti Bio's SENTI-202 CAR-NK Therapy Achieves 50% Response Rate in Relapsed/Refractory AML, Receives FDA RMAT Designation
核心洞察
Senti Bio's SENTI-202, a first-in-class Logic Gated CAR-NK cell therapy, demonstrated a 50% overall response rate and 42% complete remission rate in relapsed/refractory acute myeloid leukemia patients at the recommended Phase 2 dose.
The FDA granted SENTI-202 Regenerative Medicine Advanced Therapy (RMAT) designation, marking the second FDA recognition this year following Orphan Drug Designation in June 2025.
Clinical data showed 100% of complete remissions were MRD negative with a median duration of 7.6 months, while pharmacodynamic studies validated the therapy's selective targeting mechanism that kills cancer cells while sparing healthy bone marrow cells.
Senti Biosciences announced promising clinical results for SENTI-202, its investigational Logic Gated CAR-NK cell therapy, showing significant efficacy in treating relapsed/refractory acute myeloid leukemia (R/R AML) patients. The data, presented at the American Society of Hematology (ASH) Annual Meeting on December 8, 2025, demonstrated a 50% overall response rate (ORR) and 42% complete remission (CR)/CRh rate at the recommended Phase 2 dose (RP2D).
Clinical Efficacy Results
The Phase 1 trial enrolled 20 R/R AML patients, with 18 evaluable for response. At the RP2D, 50% (6/12) of patients achieved an overall response, while 42% (5/12) achieved complete remission or complete remission with partial hematologic recovery. Notably, 100% of all complete remissions and approximately 80% of all responses were minimal residual disease (MRD) negative.
The median duration of composite complete remissions across all patients reached 7.6 months, with the longest durability of response exceeding one year and continuing as of the data cutoff date. These results are particularly significant given the heavily pretreated patient population, where 65% had adverse risk genetics by ELN 2022 criteria and patients had received a median of two prior lines of therapy.
Mechanism of Action Validation
Pharmacodynamic data from the trial validated SENTI-202's novel OR/NOT Logic Gate mechanism. The therapy demonstrated potent AML blast killing in responders, including one patient with 90% bone marrow AML blasts at baseline. Importantly, the treatment achieved more than 10-fold killing of AML leukemic stem cells (LSCs) in ORR responders while preserving or increasing healthy hematopoietic stem and progenitor cells (HSPCs) after treatment.
"Existing cell therapies and biologic drugs have generally been limited to a subset of indications that have cancer-specific targets due to difficulty in killing cancer aggressively without triggering dangerous attacks on healthy tissues," said Timothy Lu, MD, PhD, Co-Founder and CEO of Senti Biosciences. "To overcome this longstanding key challenge, our Logic Gated cell therapies recognize and kill cancer cells based on multiple targets while simultaneously protecting healthy cells from toxicity."
Safety Profile and Tolerability
SENTI-202 demonstrated a favorable safety profile with no dose-limiting toxicities, no SENTI-202-related serious adverse events, or adverse events resulting in discontinuation. The most frequent Grade 3+ adverse events were predominantly hematologic and unrelated to SENTI-202, consistent with events observed in R/R AML patients receiving lymphodepletion. The most frequent SENTI-202-related adverse events of interest were Grade 1/2 pyrexia, likely representing delayed infusion-related reactions that resolved rapidly with standard care treatment.
FDA RMAT Designation
The FDA granted SENTI-202 Regenerative Medicine Advanced Therapy (RMAT) designation, indicating the therapy's potential to address unmet medical needs for R/R AML patients based on preliminary clinical evidence. This designation provides enhanced FDA interactions throughout development and eligibility for expedited review mechanisms including rolling and priority review.
"This significant FDA designation validates both the tremendous need for better treatments for R/R AML and the promise of SENTI-202 to transform the therapeutic landscape for this notoriously aggressive cancer," said Timothy Lu. The RMAT designation marks SENTI-202's second FDA recognition this year, following Orphan Drug Designation granted in June 2025.
Therapeutic Design and Components
SENTI-202 is designed as a first-in-class Logic Gated off-the-shelf CAR-NK cell therapy with three main components. The OR GATE is an activating CAR that recognizes and kills CD33 (搜索) and/or FLT3 (搜索) expressing cells, targeting both leukemic blasts and leukemic stem cells. The NOT GATE is an inhibitory CAR designed to recognize EMCN (搜索) selectively expressed on healthy hematopoietic stem and progenitor cells, protecting them from elimination. The therapy also contains calibrated-release IL-15 (搜索) to increase cell persistence, expansion, and activity.
Clinical Development Strategy
"The encouraging SENTI-202 data presented at ASH 2025 demonstrating deep, durable Complete Remissions and a favorable safety profile in a heavily pretreated patient population directly shapes Senti Bio's clinical development strategy," said Kanya Rajangam, M.D., Ph.D., Chief Medical Officer at Senti Bio. "This clinical evidence, together with the receipt of recent RMAT and Orphan Drug Designations from the FDA, allows us to rapidly advance SENTI-202 into pivotal studies and to explore its potential in broader patient populations that may include newly diagnosed AML, pediatric AML, and myelodysplastic syndromes (MDS)."
The ongoing multinational, multicenter dose-finding study (NCT06325748) uses a modified "3+3" design to determine the maximum tolerated dose and recommended phase two dose, followed by disease-specific expansion cohorts. Primary objectives include evaluating safety, determining dosing, and assessing efficacy using ELN 2022 consensus criteria for AML.