Abstract CT143: 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: Correlative data

Abstract SENTI-202 is being evaluated after lymphodepletion in an ongoing Phase I clinical trial, SENTI-202-101 (NCT06325748). SENTI-202 is a Logic Gated CAR NK cell therapy designed to target CD33 and/or FLT3 hematologic malignancies including acute myeloid leukemia (AML) & to spare endomucin (EMCN) expressing healthy hematopoietic stem & progenitor cells (HSPCs). Here, we report preliminary correlative data evaluating hematopoietic cell fractions in peripheral blood (PB) & bone marrow (BM) from 5 of 6 treated relapsed/refractory (R/R) AML patients with available data (6 Jan 2025). Interim clinical results are submitted as a separate abstract & additional patient data will be reported. Exploratory CyTOF analysis confirmed that all AML patients expressed the SENTI-202 CAR target CD33 (range 67-99%) & 3/5 expressed FLT3 (range 5-46%). 4 of 5 patients had blast reduction by CyTOF consistent with clinical response (3 measurable residual disease-negative complete remissions (MRD- CR) & 1 MRD+ CRh, assessed locally), after 1-2 SENTI-202 treatment cycles. To achieve deeper & longer remissions, SENTI-202 was designed to also target leukemic stem cells (LSCs), which are often FLT3+ (+/-CD33+). Preliminary CyTOF analysis showed that in responders SENTI-202 treatment resulted in a >10-fold decrease in LSCs (CD34+ CD38-/low and/or GPR56+ AML cells). Responders showed hematopoietic recovery clinically when blood counts began recovering ≥ Study Day 14 (Day 0- first dose of SENTI-202), consistent with responses, suggesting normal hematopoiesis as well as AML reduction. Repopulation of T & NK cells, neutrophils, & other immune cells, in PB collected serially post SENTI-202 was confirmed by flow cytometry. Long-term multilineage hematopoiesis requires maintenance of a healthy HSPC population, so the SENTI-202 Logic Gated Gene Circuit includes an inhibitory CAR recognizing EMCN (expressed by healthy HSPCs, rarely by AML) to protect HSPCs from potential off-tumor on-target toxicity & enable post-treatment hematopoietic recovery. Preliminary CyTOF analysis demonstrated a >10-fold increase in CD34+ CD38-/low HSPC frequencies post SENTI-202 treatment. CyTOF BM analysis also showed that some immune cell subsets (T/NK) had a higher proliferative state (increased Ki67) as well as an activated phenotype. Interim flow cytometry & CyTOF analyses of patient PB & BM in SENTI-202-101 affirms the anti-leukemic effects of SENTI-202 in responding patients, as well as the repopulation of immune cell subpopulations post-treatment. The presence of EMCN+ HSPCs in responder BM, as well as repopulation of BM & PB hematopoietic subpopulations, is consistent with the pharmacodynamic action of the Logic Gate in SENTI-202 in sparing EMCN+ HSPCs while selectively killing CD33+ and/or FLT3+ AML tumor cells. Citation Format: Muharrem Muftuoglu, Enping Hong, Stephen A. Strickland, Alireza Eghtedar, Gary Schiller, Nosha Farhadfar, Ashish R. Bajel, Farhad Ravandi, Mahesh Basyal, Li Li, Lawrence Naitmazi, Rochelle Emery, Brian S. Garrison, Timothy Lu, Kanya Rajangam, Michael Andreeff. 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: Correlative data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT143.