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

SENTI BIO #CT014 SENTI BIO #CT014 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 Stephen A. Strickland1, Alireza Eghtedar2, Nosha Farhadfar3, Ashish R. Bajel4, Farhad Ravandi5, Rochelle Emery6, Brian Garrison6, Muharrem Muftuoglu5, Michael Andreeff5, Kanya Rajangam6, Gary Schiller7 1SCRI at TriStar Centennial, Nashville, TN, 2Colorado Blood Cancer Institute, Denver, CO, 3Sarah Cannon Transplant and Cellular Therapy Program at Methodist Hospital San Antonio, TX, 4Peter MacCallum Cancer Centre, Melbourne, Australia,5The University of Texas M.D. Anderson Cancer Center, Houston, TX, 6Senti Biosciences, Inc, South San Francisco, CA,7David Geffen School of Medicine at UCLA, Los Angeles, CA SENTI BIO #CT014 SENTI BIO #CT014 Stephen Strickland, MD I have the following relevant financial relationships to disclose: Employee of: HCA Healthcare In addition, payments were made to Sarah Cannon Research Institute, SCRI for my work, no personal compensation was received from any of these companies. Consultant for: AbbVie, Caribou, Genentech, Kura Oncology, Novartis, SentiBio, Sobi, Sumitomo, Syros, Terns within the past 24 months Speaker’s Bureau for: GSK Grant/Research support: Beam, Caribou, Cellectis, Janssen, KumquatBio, Kura Oncology, Novartis, Oryzon, Schrodinger, SentiBio, Stemline, Syros, Systimmune, Takeda, Terns, Vincerx, Vironexis, and Zentalis Stockholder in: None Honoraria from: None Disclosure Information SENTI BIO #CT014 SENTI BIO #CT014  20,800 newly diagnosed AML patients in US every year1 • ~60% patients experience relapse or death within 12 months2 Acute Myeloid Leukemia (AML) Is an Aggressive Leukemia with Poor Prognosis  Current standard of care responses4,5 • CR rate ~15-25% • CR/CRh rate ~20-33% AML Estimated Disease Burden Relapsed/Refractory AML Patient Outcomes Median survival of 5.3 months3 5-year survival rate is 12.6%3 Effective Anti-AML Therapies Need To: CR: complete remission; CRh: complete remission with partial hematologic recovery; MRD: measurable residual disease; HSC: hematopoietic stem cell 1SEER 2024; 2Tenold Frontiers in Oncology 2021; 3Brandwein AJBR 2020; 4Dohner Blood 2022; 5USPI Idhifa, Xospata, Tibsovo; 6Zeijlemaker Leukemia 2019; 7Innes Blood 2018 To achieve deep / MRD negative CR Leading to durable remissions / longer survival4,6 Selectively kill AML blasts & LSCs, and spare HSCs2 To support normal blood cell count recovery Target heterogenous clones / leukemia stem cells (LSCs)61 Leading to improved prognosis / longer survival7 SENTI BIO #CT014 SENTI BIO #CT014  OR Logic Gate “Kills” leukemia blasts and LSCs via CD33 OR FLT3 activating CAR (aCAR) • CD33 and/or FLT3 expressed in ~95% of AML patients with CD33 being predominantly expressed on bulk blasts and FLT3 on LSCs  NOT Logic Gate “Protects” healthy HSC/HSPCs from ‘off- tumor, on-target’ effects • Protection of HSC/HSPCs via NOT Endomucin (EMCN) inhibitory CAR (iCAR) even when they express CD33 and/or FLT3 • EMCN found predominantly on healthy HSC/HSPC surface, rarely on AML blasts  Calibrated release IL-15 “Enhances” SENTI-202 and host immune cell activity and persistence SENTI-202 is a First-in-Class Off-the-Shelf Logic Gated Selective CD33 OR FLT3 NOT EMCN CAR NK Cell Therapy for Blood Cancers Bivalent CD33 and/or FLT3 activating CAR Calibrated release IL- 15 Endomucin inhibitory CAR to protect healthy cells Persistence, activation of CAR-NK and immune cells Healthy NK cells from selected adult donors FLT3 EMCN CD33 Healthy cell protection HSC aCAR iCAR Host immune cell SENTI-202 Cancer cell killing Blast cell CD33 LSC FLT3 SENTI-202 is designed to selectively kill both AML blasts and LSCs while protecting healthy HSC/HSPCs using its novel CD33 OR FLT3 NOT EMCN logic gated gene circuit SENTI-202 Gene Circuit Design LSC: Leukemia stem cell; HSC: hematopoietic stem c ell; HSPC: hematopoietic stem and progenitor cell SENTI BIO #CT014 SENTI BIO #CT014 SENTI-202 Scalable Manufacturing Process Off-the-Shelf Allogeneic CAR-NK Len tivir us Outpatient use potential Isolate from selected donors Thaw and Infuse Off-the-Shelf Scalable Process NK Cells Selected Donor Engineer Cryopreserve and Store Expand SENTI-202 Gene Circuit delivered through single transduction step 1 2 3 4 1 Easy to thaw vials Final product harvested and cryopreserved NK cells isolated from peripheral blood of selected donors NK cells efficiently engineered with Gene Circuits High post- thaw potency Gene Circuit Engineered CAR-NK cells Patient SENTI BIO #CT014 SENTI BIO #CT014 SENTI-202 Phase 1 Trial (SENTI-202-101) Design A multicenter, multinational, open-label study (NCT06325748)  ≥18 and <75 years  ECOG 0-1  R/R CD33 and/or FLT3 expressing heme malignancies • CD33+ by local assessment  R/R AML (1-3 prior Rx)  R/R MDS with increased blasts1(1-2 prior Rx)  Must have received targeted agents if applicable mutations Key Eligibility Criteria  Primary objective- safety and determination of MTD/RP2D  DLT definition includes: • ≥ G3 non-hematologic toxicities • Prolonged G4 neutropenia/ thrombocytopenia not due to underlying disease  Other key objectives • Efficacy based on ELN 2022 criteria (AML) • MRD assessed per local standard of care • Pharmacokinetics (PK) • Pharmacodynamics (PDn) using CyTOF on serial BM samples Study Objectives ECOG: European Cooperative Oncology Group; RP2D: recommended phase 2 dose; MTD: Maximum tolerated dose; DLT: dose limiting toxic ity; G: Grade by CTCAE v5.0 and other applicable Grading systems; ELN: European LeukemiaNet; CyTOF: Cytometry by Time-of-Flight; BM: bone marrow 1Per WHO 2022 Classification; Study Design “3+3” Dose finding followed by AML, MDS and other expansion cohorts at RP2D Study Dosing 2 Dose Levels and 2 Schedules Opening dose cohort was anticipated to be biologically active SENTI BIO #CT014 SENTI BIO #CT014 SENTI-202 Phase 1 Trial (SENTI-202-101) Dosing Schema- Preliminary RP2D Identified 1 28Day -7 to -3 0 7 14 SENTI-202 Dose Schedule Efficacy Assessment Multiple cycles allowed to achieve optimal response Multi-Dose Cycle Lymphodepletion Fludarabine/ Cytarabine (Ara-C) 28Day -7 to -3 0 3 7 10 14 Dose SCHEDULE I SCHEDULE II Dose Level CAR+ NK Cells/Dose 1 1 x 109 2 1.5 x 109 SENTI-202 Dose Levels Opening Dose Cohort was Anticipated to be Biologically Active Schedule I Dose Level 1, N = 3 No DLTs Schedule I Dose Level 2, N = 3 No DLTs Identified as preliminary RP2D based on totality of clinical data Schedule II Dose Level 1, N = 3 No DLTs SENTI BIO #CT014 SENTI BIO #CT014 preliminary RP2D Study Enrolled a High-Risk R/R AML Population with Multiple Baseline Adverse Characteristics Baseline Characteristics Dose Level 1 Dose Level 2 All Patients N = 9Schedule I N = 3 Schedule II N = 3 Schedule I N = 3 Age, yr, median (range) 64 (26,72) 41 (36, 67) 63 (51, 69) 63 (26, 72) Male, n (%) 1 (33) 2 (67) 3 (100) 6 (67) AML, n (%) 3 (100) 3 (100) 3 (100) 9 (100) Years from AML diagnosis, median (range) 2.84 (0.5, 6.2) 0.49 (0.3, 0.8) 0.94 (0.5, 1.0) 0.75 (0.3, 6.2) Adverse risk by ELN 2022, n (%) 2 (67) 2 (67) 3 (100) 7 (78) Baseline bone marrow blasts, %, median (range) 20 (15, 69) 30 (18, 31) 45 (10, 93) 30 (10, 93) Baseline platelet count < 50 x 109/L , n (%) 0 (0) 2 (67) 2 (67) 4 (44) Data from an open clinical database of an ongoing study as of 7 Apr 2025 • Median of <1 yr from diagnosis to trial entry across all patients and in preliminary RP2D cohort • Majority of patients (all in preliminary RP2D cohort) with adverse risk genetics by ELN 2022 criteria SENTI BIO #CT014 SENTI BIO #CT014 preliminary RP2D Study Subjects had Received Multiple Prior Therapies Prior Therapy Dose Level 1 Dose Level 2 All Patients N = 9Schedule I N = 3 Schedule II N = 3 Schedule I N = 3 Number of prior lines, median (range) 1 (1,1) 2 (1, 2) 2 (2, 3) 2 (1,3) Chemotherapy, n(%) 3 (100) 3 (100) 3 (100) 9 (100) Fludarabine and/or Ara-C, n (%) 3 (100) 3 (100) 3 (100) 9 (100) Anthracycline, n (%) 3 (100) 2 (67) 3 (100) 8 (89) Venetoclax, n (%) 1 (33) 3 (100) 3 (100) 7 (78) Hypo-methylating Agents, n (%) 2 (67) 3 (100) 3 (100) 8 (89) FLT3/IDH2 targeted therapy, n (%) 1 (33) 1 (33) 1 (33) 3 (33) Bone marrow transplant, n (%) 1 (33) 0 (0) 1 (33) 2 (22) Primary refractory*, n (%) 1 (33) 2 (67) 2 (67) 5 (56) Data from an open clinical database of an ongoing study as of 7 Apr 2025; * Primary refractory defined as failure to achieve cCR or cCR lasting <3 mo with front-line therapy • Median of 2 lines before study entry overall and in preliminary RP2D cohort • All patients with previous chemotherapy exposure including fludarabine and/or cytarabine (4 received both) and majority with previous venetoclax exposure SENTI BIO #CT014 SENTI BIO #CT014 preliminary RP2D Patients Received a Median of 2 Cycles of SENTI-202 Therapy Exposure Dose Level 1 Dose Level 2 All Patients N = 9Schedule I N = 3 Schedule II N = 3 Schedule I N = 3 Number of SENTI-202 treatment cycles, median (range) 2 (1, 2) 2 (1, 2) 2 (1, 2) 2 (1, 2) Subjects continuing treatment as of data-cut, n (%) 0 2 (67) 0 2 (22) Subjects discontinuing treatment, n (%) 3 (100) 1 (33) 3 (100) 7 (78) Adverse Event 0 0 0 0 Achieved Optimal Response (cCR) 2 (67) 0 2 (67) 4 (44) Disease Progression/ Stable Disease 1 (33) 1 (33) 1 (33) 3 (33) Data from an open clinical database of an ongoing study as of 7 Apr 2025; cCR: composite CR includes CR, CRh, CRi • Median of 2 cycles across dose cohorts • Majority of patients discontinued SENTI-202 after achieving cCR with none discontinuing due to adverse event SENTI BIO #CT014 SENTI BIO #CT014 preliminary RP2D Preliminary Safety Data Indicate that SENTI-202 is Well Tolerated Any Grade 3-4* AEs Regardless of Relationship Dose Level 1 Dose Level 2 All Patients N = 9Schedule I N = 3 Schedule II N = 3 Schedule I N = 3 Any Grade ≥ 3 AEs 3 (100) 3 (100) 3 (100) ^ 9 (100) Febrile Neutropenia 1 (33) 1 (33) 2 (67) ^ 4 (44) Platelet Count Decreased 2 (67) 0 2 (67) ^ 4 (44) Anemia 1 (33) 1 (33) 0 2 (22) Abdominal Pain 1 (33) 1 (33) 0 2 (22) *No Grade 5 AEs, ^ 1 patient with G3 febrile neutropenia and G4 platelet count decreased assessed as possibly related to SENTI-202 AEs: treatment emergent adverse events includes adverse events with onset after SENTI -202 dosing and within 30 days of last dose of study treatment; Grading per CTCAE v5.0 Data from an open clinical database of an ongoing study as of 7 Apr 2025 SENTI-202 was well tolerated • In general, G3-4 AEs on study were hematologic, unrelated to SENTI-202 and consistent with R/R AML patients receiving LD • No single type of SAE reported in > 1 patient • No significant difference in AE profile across dose cohorts SENTI BIO #CT014 SENTI BIO #CT014 SENTI-202 Related AEIs Were Low Grade and Manageable with Standard of Care Patient # (Dose Cohort) Event Term (Grade) Onset from SENTI-202 Dose (days) Duration (days) 001-0004, (1) Chills, G1 0 1 Pyrexia, G1 0 1 008-005, (1) Pyrexia, G1 0 5 Hypotension, G1 3 1 102-007, (prelim. RP2D) Pyrexia, G1 1 1 Hypoxia, G2 1 1  3 pts experienced G1 pyrexia with either hypotension or hypoxia in 1 each, typically within 1 day of SENTI -202 dosing that were reported as Cytokine Release Syndrome (CRS) • Events resolved rapidly with standard of care; None were serious  Likely represent delayed infusion reactions described with NK cell therapies  No other AEIs or DLTs reported on study AEIs: AEs of Interest; Grading per ASTCT criteria Data from an open clinical database of an ongoing study as of 7 Apr 2025 SENTI BIO #CT014 SENTI BIO #CT014 preliminary RP2D Responses Observed Across All Dose Cohorts Best Overall Response on Study, n (%) Dose Level 1 Dose Level 2 All Patients N = 7*Schedule I N = 3 Schedule II N = 1* Schedule I N = 3 Overall Response Rate (ORR) 2 (67) 1 (100) 2 (67) 5 (71) composite CR Rate (cCR)^ 2 (67) 0 2 (67) 4 (57) Negative MRD Status in cCR Patients 2/2 (100) N/A 2/2 (100) 4/4 (100) Response Category, n(%) CR 2 (100) 0 1 (33) 3 (43) CRh 0 0 1 (33) 1 (14) MLFS 0 1 (100) 0 1 (14) SD 0 0 1 (33) 1 (14) PD 1 (33) 0 0 1 (14) *Two patients continuing into second Cycle after achieving SD with blast reduction from 31% to 13% and 5% to 3% respectively are excluded from best overall response assessment; ^CR + CRh + CRi Data from an open clinical database of an ongoing study as of 7 Apr 2025 AML Response  5 of 7 patients overall achieved ORR  2/3 and 4/7 patients achieved cCR respectively in preliminary RP2D cohort and across all patients  4/4 cCR patients were MRD-  All cCR responses are ongoing as of data-cut with median duration of response not reached SENTI BIO #CT014 SENTI BIO #CT014 Rapid Bone-Marrow Blast Reduction Observed Across All Dose Cohorts Data from an open clinical database of an ongoing study as of 7 Apr 2025 Blast reduction noted in majority of patients across all dose cohorts Total Bone Marrow Blasts (%) * End of cycle 1 for patients 8 and 9 * 100 80 60 40 20 0 Baseline Best Response SENTI BIO #CT014 SENTI BIO #CT014 preliminary RP2D 0 30 60 90 120 150 180 210 240 270 300 330 360 SD SD Early Deep Responses Noted Across Dose Levels with Durability 8+ months I0 Ref: Primary refractory defined as f ailure to achieve cCR or cCR lasting <3 mo with front-line therapy; Adv. Risk: Adverse Risk genetics by ELN 2022; FA Exp: fludarabine and/or Ara- C Exposed, both indicates exposed to both agents; FA Ref: Fludarabine and/or Ara- C refractory (failure to achieve cCR or cCR lasting < 3 mo), both indicates refractory to both agents; #Patient had detectable IDH2 mutation by NGS while in morphologic remission and started on venetoclax /enasidenib; Data from an open clinical database of an ongoing study as of 7 Apr 2025 0 30 60 90 120 150 180 210 CR MRD-* CR MRD+# 5+ mo. CR CRh MRD+* CRh MRD-* HCT 4+ mo. CR SD No response PR CR MRD-** HCT 8+ mo. CR CR MRD-* HCT 7+ mo. CR PD Death MLFS MRD+* PD ^ Cycle 1 ^^ Cycle 2 ^ ^^ ^ ^^ ^ ^^ ^Cycle1 ^^ Cycle 2 ^ ^^ ^ ^ ^ Days Days *MRD by multi-parametric flow (sensitivity ≤ 1/10-4), **MRD by NGS (sensitivity ≤ 1/10-2) Pt I0 Ref Adv. Risk FA Exp FA Ref Pt1 No Yes Yes No Pt2 No No Yes No Pt3 Yes Yes Yes Yes Pt7 Yes No Yes- both Yes- both Pt8 Yes Yes Yes Yes Pt9 Unk Yes Yes- both Unk Pt I0 Ref Adv. Risk FA Exp FA Ref Pt4 Yes Yes Yes- both Yes- both Pt5 No Yes Yes- both No Pt6 Yes Yes Yes Yes SENTI BIO #CT014 SENTI BIO #CT014 CyTOF Bone Marrow Data Reveals SENTI-202 Treatment Results in Decreased LSCs in Responders LSC (CD34+ CD38low) in Bone Marrow Baseline C1D28 C2D28 100 10 1 0.1 0.01 0 • CyTOF measured 49 different proteins in serial bone marrow derived mononuclear cells samples from baseline and end of each Cycle • At baseline, majority of leukemia stem cells (LSCs) were in G0 phase and not expected to be susceptible to chemotherapy • With SENTI-202 treatment, LSCs decreased > 10-fold in all patients who achieved cCR IdU: 5-Iodo-2’-Deoxyuridine; Data from an open clinical database of an ongoing study as of 7 Apr 2025 % CD34+ CD38low LSC of AML cells * * Subject 5 samples had low viability LSCs in bone marrow at baseline are largely non- cycling when analyzed by Ki67 and IdU SENTI BIO #CT014 SENTI BIO #CT014 Rapid Normalization of Peripheral Blood Cell Count along with Protection of BM HSPCs in Patients who Achieved cCR Data from an open clinical database of an ongoing study as of 7 Apr 2025 Baseline C1D28 C2D28 HSPC (CD34+ CD38low) in Bone Marrow (BM) %CD34+ CD38low HSPC of all cells 0.001 0.1 1 10 0.01 100 * Patient 5 samples had low viability. Rapid blood cell count recovery in periphery in patients who achieved cCR • Median of 21 days for neutrophil count ≥ 0.5 and 1 x109/ L, and 28/35 days to platelet count ≥ 50 and 100 x109/ L • CyTOF analyses revealed HSPCs were maintained or increased in bone marrow of patients who achieved cCR consistent with SENTI-202 Logic Gate mechanism of action 0 0.5 1 1.5 2 2.5 0 50 100 150 200 250 -7 0 7 14 21 28 Absolute Neutrophil Count (x 109/ L) Platelet Count (x 109/ L) Days Peripheral Blood Cell Counts * SENTI BIO #CT014 SENTI BIO #CT014 Senti-202 Is Detected in Periphery of All Treated Patients Consistent with Allo-NK Profile Cycle 1 LLOQ Copies/μg DNA Time (Days) 0 100 1000 10,000 7 14 21 28 0 100 1000 7 14 21 28 LLOQ 10,000 Cycle 2  PK profile consistent with allogeneic NK cell therapy • Modest peripheral expansion in first 14 days consistent with NK biology and safety of SENTI-202 • Clearance >14 days from periphery  No significant difference in exposure across patients who achieved cCR or not  No significant difference in exposure across Dose Cohorts  No significant difference in exposure between Cycle 1 and 2 Interim PK data as of 7 Apr 2025; value of 1 assigned for timepoints with non-measurable transgene, LLOQ estimated using equivalent DNA loading and is the lower limit of quantitation SENTI BIO #CT014 SENTI BIO #CT014  SENTI-202 is a First-In-Class Off-the-Shelf Logic Gated selective CD33 OR FLT3 NOT EMCN CAR NK cell therapy • Designed to selectively kill both AML blasts and LSCs while protecting healthy HSPCs with a novel OR/NOT logic gated gene circuit  SENTI-202-101 trial enrolled heavily treated R/R AML patients with poor prognosis  SENTI-202 is well tolerated • Most frequent Grade 3+ AEs were hematologic and consistent with R/R AML patients receiving LD • MTD not reached and preliminary RP2D identified as 1.5B cells/ dose x 3 weekly doses/ 28 days Dosing and Safety Conclusions- SENTI-202 Well Tolerated in R/R AML Patients SENTI BIO #CT014 SENTI BIO #CT014  Efficacy • 5/7 ORR and 4/7 cCR across all patients including 2/3 cCR in preliminary RP2D cohort • 4/4 cCR MRD- as assessed per local standard of care • All cCR patients maintaining morphologic remission with longest follow up of 8+ mo  PK • SENTI-202 detected in all treated patients, consistent with other allogeneic CAR NK cell therapy PK profiles and its well-tolerated safety profile  CyTOF analyses of BM • SENTI-202 treatment decreased LSC frequencies and maintained (or increased) healthy HSPC frequencies in patients achieving cCR consistent with SENTI-202 Logic Gated gene circuit design Efficacy Conclusions- Promising Preliminary Efficacy Noted with SENTI-202 in R/R AML Patients SENTI BIO #CT014 SENTI BIO #CT014  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 (#10977) Session: PO.CT01.02 - First-in-Human Phase I Clinical Trials 2 Location: Section 48, #9 Time: 4/29/2025 9:00:00 - 12:00:00 PM  SENTI-202 CD33 OR FLT3 NOT EMCN Logic-Gated Gene Circuit Components Selectively Target AML while Protecting Human HSC/HPCs from Off-Tumor Toxicity in a Humanized Mouse Model (#6833) Session: PO.IM01.17 - Novel In Vivo, In Vitro, and In Silico Models Location: Section 38, #18; Time: 4/30/2025 9:00:00 - 12:00:00 PM Also at AACR… SENTI BIO #CT014 SENTI BIO #CT014  We deeply appreciate our Patients and their caregivers  Clinical and research staff at all participating Institutions • United States: o SCRI at TriStar Centennial, Nashville, TN o Colorado Blood Cancer Institute, Denver CO o Methodist Physician Practices, PLLC, San Antonio o The University of Texas M.D. Anderson Cancer Center, Houston, TX o UCLA Department of Medicine, Los Angeles, CA • Australia: o Peter MacCallum Cancer Center, Melbourne, Australia  Senti Biosciences, our Sponsor and the developer of SENTI-202  California Institute of Regenerative Medicine (CIRM) for partially funding the study Acknowledgements

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