DARIC33 / Seattle Children’s Therapeutics, Regeneron - LARVOL DELTA

Drug-regulated CD33-targeted CAR T cells control AML using clinically optimized rapamycin dosing. (PubMed, J Clin Invest) - P1 | "A phase 1 DARIC33 trial has been initiated (PLAT-08, NCT05105152), with initial evidence of rapamycin-regulated T cell activation and anti-tumor impact. Our findings provide evidence that the DARIC platform exhibits sensitive regulation and potency needed for clinical application to other important immunotherapy targets."

CAR T-Cell Therapy • Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD33 • CD34

PLAT-08: A Study Of SC-DARIC33 CAR T Cells In Pediatric And Young Adults With Relapsed Or Refractory CD33+ AML (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: Seattle Children's Hospital | Trial completion date: Jan 2039 ➔ Jan 2041 | Trial primary completion date: Feb 2024 ➔ Feb 2026

CAR T-Cell Therapy • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • CD33

2seventy bio Announces Clinical Study Pause of PLAT-08 Trial of SC-DARIC33 in Acute Myeloid Leukemia (Businesswire) - "2seventy bio...announced that the Phase 1 trial of the PLAT-08 study of SC-DARIC33 in Acute Myeloid Leukemia (AML) has been paused by Seattle Children’s, the Company’s partner and the regulatory sponsor of the study. The pause was instituted as part of the clinical study protocol stopping rules in response to a recent Grade 5 (fatal) serious adverse event (SAE) and was followed by the required notification to the U.S. Food & Drug Administration (FDA). The root cause of this SAE and its potential relationship to the study drug is currently under investigation....The SAE occurred in the first patient treated at the second dose level in the Phase 1 trial."

Trial suspension • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

2seventy bio Presents Late-Breaking Results for SC-DARIC33, an Investigational CD33-Targeting CAR T in Pediatric and Young Adults with Relapsed or Refractory Acute Myeloid Leukemia (Businesswire) - P1 | N=18 | PLAT-08 (NCT05105152) | "2seventy bio... announced late-breaking results from the ongoing Phase 1 PLAT-08 trial, in collaboration with Seattle Children’s Therapeutics, evaluating SC-DARIC33 in relapsed or refractory pediatric and young adult AML patients, as well as an oral presentation evaluating regulated IL-15 production combined with DARIC33 activation for anti-AML potency. The data were presented at this year’...ASGCT Annual Meeting....As of March 17, 2023, three participants had received cell product infusion at 1 x 106 SC-DARIC33 T cells /kg (dose level 1) following LD chemotherapy. Infusions were generally well tolerated without occurrence of dose-limiting toxicities....In a separate oral presentation, researchers evaluated whether regulated IL-15 production combined with drug-controlled DARIC33 activation could enhance anti-AML potency without driving uncontrolled T cell growth or severe toxicity in the preclinical setting."

Late-breaking abstract • P1 data • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

2seventy bio Presents Broad Range of New Data Highlighting Novel Approaches Across its Cell Therapies Portfolio (Businesswire) - "The RESET receptor comprises two functional units that are designed to enable toggling of RESET T cells between inert and activated states through rapamycin-induced dimerization: When challenged with low antigen density tumor cells in vitro, CD33-targeted RESET T cells (RESET33) were more potently reactive to CD33+ tumor cells after rapamycin dimerization, secreting approximately three times more cytokine than CD33-targeted regulated CAR T cells. This enhancement was also observed in preclinical NSG mouse models in vivo, where RESET33 T cells more deeply controlled systemic CD33+ AML tumor models, providing a significant survival benefit in comparison to DARIC33 T cells....In two murine xenograft tumor models with abundant TGFβ, T cells co-expressing the MAGE-A4 TCR and CTBR12 both controlled tumors at T cell doses that elicited only minimal responses without CTBR12 co-expression and exhibited superior durability of response overall."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

First in Human Studies Show Activation of SC-DARIC33, a Rapamycin-Regulated Anti-CD33 CAR T Cell Therapy, in Patients with AML (ASGCT 2023) - P1 | "Following lymphodepletion (LD) with fludarabine/cyclophosphamide, patients received SC-DARIC33 T cells on day 0 followed by RAPA on days 2-21, targeting trough levels of 1.5-3ng/mL to activate SC-DARIC33. These results demonstrate successful RAPA regulated activation of SC-DARIC33 T cells in patients, resulting in expansion and concurrent anti-CD33 activity. PLAT-08 enrollment is ongoing with plans for evaluation of two additional dose levels (5 and 10 x 106 SC-DARIC33 T cells/kg). Future work will focus on understanding SC-DARIC33 T cell activation"

CAR T-Cell Therapy • Clinical • IO biomarker • Late-breaking abstract • P1 data • Acute Myelogenous Leukemia • HAVCR2 • PD-1 • TNFRSF9

RESET: A Novel TCR Coupled Antigen Receptor Displaying Superior Targeting Sensitivity and Pharmacologically Controlled Anti-Tumor Activity (ASGCT 2023) - "Here, we describe a novel receptor architecture called RESET (rapamycin-enabled, switchable endogenous TCR) that combines: (i) the antibody-based targeting of CARs; (ii) the drug-regulated activity of the DARIC technology (a "drug on" CAR T system); and (iii) the natural signaling proficiency and inherent sensitivity of TCRs.The RESET receptor comprises two functional units that enable toggling of RESET T cells between inert and activated states through rapamycin-induced dimerization...This enhancement was also observed in preclinical NSG mouse models in vivo, where RESET33 T cells more deeply controlled systemic CD33+ AML tumor models, providing a significant survival benefit in comparison to DARIC33 T cells...The convergence of drug regulated antigen targeting and natural immune receptor signaling may better replicate the kinetics and physiology of T cell responses, resulting in more successful immunotherapies. Taken together, these data support the clinical..."

IO biomarker • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Oncology • CD33 • FKBP5

Enhanced Anti-AML Potency of DARIC33 by iSynPro-IL-15*: An IL-15 Expression Module Driven by a Tightly Regulated Synthetic Promoter Activated by Antigen Receptor Signaling (ASGCT 2023) - "INTRODUCTION: DARIC33, a dimerizing agent regulated immunoreceptor complex targeting CD33 that requires low doses of rapamycin (RAPA) for activity, is being studied in an ongoing phase 1 clinical trial (NCT 05105152). We find iSynPro-IL-15* retains properties of inducible expression and potency enhancement. Our results suggest that the triple safety features of iSynPro-regulated expression, IL-15* safety modification, and RAPA controlled DARIC33 activation prevent unrestrained T cell outgrowth. We believe this potency enhancement strategy will be applicable to next generation clinical AML CAR T cell therapeutics."

Acute Myelogenous Leukemia • Oncology • CD33 • CD8 • IL15 • IL2

2seventy bio to Present New Preclinical and Clinical Data from Broad Portfolio of Investigational Cell Therapies at the ASGCT 26th Annual Meeting (Businesswire) - "2seventy bio...announced the presentation of five abstracts, including one late-breaking oral presentation, at this year’s American Society of Gene & Cell Therapy (ASGCT) Annual Meeting....The late-breaking abstract featuring early findings from the ongoing Phase 1 PLAT-08 trial in collaboration with Seattle Children’s Therapeutics, evaluating SC-DARIC33 in pediatric and young patients with relapsed/refractory AML, will be presented on Friday, May 19....A second oral presentation will feature preclinical data on enhanced anti-AML potency of DARIC33 by coupling it with iSynPro-IL-15, an encoded IL-15 expression module driven by an antigen-regulated synthetic promoter that will be presented on Thursday, May 18."

Late-breaking abstract • P1 data • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

2seventy bio Reports Fourth Quarter and Full Year 2022 Financial Results and Recent Operational Progress (Businesswire) - “PIPELINE: Data update from Phase I CRC-403 study of bbT369 in patients with relapsed and/or refractory B cell non-Hodgkin lymphoma (B-NHL) anticipated by the end of 2023; Data update from Phase I PLAT-08 study of SC-DARIC33 in patients with acute myeloid leukemia by the end of 2023; Submission of an IND for MUC-16 program in ovarian cancer, being developed in partnership with Regeneron by end of 2023; Led by JW Therapeutics, initiation of an investigator-initiated study in China of 2seventy bio’s potency enhanced MAGE-A4 TCR program in solid tumors by end of 2023.”

IND • New trial • P1 data • Acute Myelogenous Leukemia • Gynecologic Cancers • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Solid Tumor

2seventy bio Reports Third Quarter Financial Results and Recent Operational Progress (Businesswire) - "2seventy bio’s clinical studies of DARIC-33 in acute myeloid leukemia (AML) and bbT369 in B cell non-Hodgkin lymphoma (B-NHL) are open and enrolling. We plan to share clinical data from these programs in the future. The company continues to execute pre-investigational new drug (IND) work to support a MUC-16 IND in 2023."

IND • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Non-Hodgkin’s Lymphoma • Oncology

Pediatric and young adult leukemia adoptive therapy (PLAT)-08: A phase 1 study of SC-DARIC33 in pediatric and young adults with relapsed or refractory CD33+ AML. (ASCO 2022) - P1 | "These subunits remain inactive until the administration of rapamycin which allows for dimerization of the subunits, enabling T cell activation when antigen is present. The trial will implement a BOIN design with three possible dose levels (1 x 106, 5 x 106, and 10 x 106 DARIC+ cells/kg) to determine the maximum tolerated dose (MTD). The trial is open for enrollment at Seattle Children’s Hospital."

Clinical • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Inflammation • Leukemia • Oncology • Pediatrics • CD33

2seventy bio Reports Fourth Quarter and Full Year 2021 Financial Results and Recent Operational Progress (Businesswire) - "KarMMa-2 study in high-risk multiple myeloma proof-of-concept data in 2022, KarMMa-3 study in 3L+ registrational data in 2023 with potential FDA approval in 2023-2024...Presentation of preclinical data from bbT369 program in B-NHL at AACR Annual Meeting 2022. Infusion of first patients in CRC-403 study of bbT369 in B-NHL in 2022. Initial assessment of feasibility of bbT369 drug product manufacturing and patient safety in 2H 2022. Infusion of first patients in PLAT-08 study of SC-DARIC33 in AML in 2022. Initial assessment of feasibility of SC-DARIC33 drug product manufacturing and drug regulated anti-CD33 activity in 2H 2022."

FDA event • P2 data • P3 data • Preclinical • Trial status • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

2seventy bio Shares Key Milestones and Business Updates for 2022 (Businesswire) - "UPCOMING ANTICIPATED MILESTONES: ABECMA - Anticipate $250-300M total U.S. revenue in 2022. Increasing manufacturing capacity throughout 2022. KarMMa-2 study in 2L proof-of-concept data in 2022. KarMMa-3 study in 3L+ registrational data in 2023; Pipeline: Infusion of first patients in PLAT-08 study of SC-DARIC33 in AML in 2022. Initial assessment of feasibility of SC-DARIC33 drug product manufacturing and drug regulated anti-CD33 activity in 2H 2022. Infusion of first patients in CRC-403 study of bbT369 in B-NHL in 2022. Initial assessment of feasibility of bbT369 drug product manufacturing and patient safety in 2H 2022."

Clinical data • Trial status • Acute Myelogenous Leukemia • Hematological Malignancies • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

PLAT-08: A Study Of SC-DARIC33 In Pediatric And Young Adults With Relapsed Or Refractory CD33+ AML (clinicaltrials.gov) - P1; N=18; Recruiting; Sponsor: Seattle Children's Hospital; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • CD33

Seattle Cancer Care Alliance Clinicians Present New Research at 63rd Annual Meeting of the American Society of Hematology (Businesswire) - "Seattle Cancer Care Alliance (SCCA)...announced that more than 20 of the organization’s clinicians will showcase new research at the 63rd Annual Meeting of the American Society of Hematology (ASH), taking place December 11-14, 2021, in Atlanta....Clinicians will discuss findings on CAR-T therapies targeting CD20 cells, multiple myeloma and chronic lymphocytic leukemia. Key research also includes findings on hematopoietic stem cell transplant (HCT) and outcomes and utilization for a range of treatments."

Clinical data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Non-Hodgkin’s Lymphoma • Oncology

Clinical Translation of SC-DARIC33: A Pharmacologically Controlled CD33-Targeted Anti-AML CAR T Cell Product Regulated By Low Nanomolar Concentrations of Rapamycin (ASH 2021) - "Evaluation of GMP cell products and RAPA PK demonstrate that very low doses of RAPA are sufficient to regulate SC-DARIC33. To establish safety of SC-DARIC33 in humans, an upcoming phase 1 trial clinical trial evaluating SC-DARIC33 in pediatric AML patients will test escalating cell doses followed by low-dose RAPA administration from post T cell infusion days 2-21 using a Bayesian optimal interval (BOIN) design. Peripheral blood samples will be monitored for CD33+ myeloid cell recovery after cessation of RAPA dosing."

CAR T-Cell Therapy • Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • CCR7 • CD19 • CD27 • CD33 • CD8 • IFNG • IL15 • IL2 • IL21 • IL7 • TNFA

2seventy bio Presents Data Across Multiple Cell Therapy Programs at ASH 2021 Annual Meeting (Businesswire) - "Potentially First-in-Class Autologous T Cell Therapy Exploring an Innovative Approach to Acute Myeloid Leukemia (AML): An oral presentation (#905), in collaboration with Seattle Children’s Therapeutics, showcased data that demonstrate the regulatability and anti-AML activity of SC-DARIC33 in a preclinical setting."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

2seventy bio Reports Third Quarter Financial Results and Recent Operational Progress (Businesswire) - "Today, 2seventy bio is announcing that the FDA has accepted the IND for SC-DARIC33, an investigational, pharmacologically controlled CD33-targeted autologous T cell product, developed in collaboration with Seattle Children’s Therapeutics for the potential treatment of acute myeloid leukemia (AML). PLAT-08, the Phase 1 study of SC-DARIC33 in relapsed/refractory pediatric AML, led by Seattle Children’s Therapeutics, is now open and enrolling patients (NCT: 05105152)."

IND • Trial status • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

2seventy bio Reports Third Quarter Financial Results and Recent Operational Progress (Businesswire) - "UPCOMING ANTICIPATED MILESTONES: (i) Acceptance of investigational new drug (IND) application for bbT369 in bNHL by the end of 2021; (ii) Presentation of new preclinical data from the SC-DARIC33 program at the 63rd ASH Annual Meeting in December 2021; (iii) Presentation of clinical data from the ongoing CRB-402 study of bb21217 at the 63rd ASH Annual Meeting in December 2021."

IND • P1 data • Preclinical • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

2seventy bio Completes Spin Transaction and Launches Innovative Immuno-oncology Cell Therapy Company (Businesswire) - "Acute Myeloid Leukemia (AML)/SC-DARIC33: The initiation of an upcoming Phase 1 study of SC-DARIC33 in relapsed/refractory pediatric and young adult AML in collaboration with Seattle Children’s Therapeutics will be a first-in-human investigation of 2seventy bio’s proprietary Dimerizing Agent Regulated Immunoreceptor Complex (DARIC) T cell platform; B-cell non-Hodgkins Lymphoma (bNHL)/bbT369: The initiation of an upcoming Phase 1 dose-escalation study in patients with relapsed and refractory bNHL will be a proof-of-concept study of 2seventy bio’s proprietary gene editing platform, dual-targeting strategies and split co-stimulation signaling technology."

New P1 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

2seventy bio Completes Spin Transaction and Launches Innovative Immuno-oncology Cell Therapy Company (Businesswire) - "2seventy bio...announced its official launch as an independent, publicly traded company. 2seventy bio will trade on the Nasdaq Global Select Market, commencing tomorrow, November 5 under the ticker symbol 'TSVT'....The company officially separates today from bluebird bio, Inc. and launches with a robust cell therapy pipeline across a range of hematologic and solid tumors including two candidates that are planned to enter the clinic in the first half of 2022. The portfolio also includes a development and 50/50 U.S. commercialization partnership with Bristol Myers Squibb (BMS) for ABECMA..."

Commercial • Hematological Malignancies • Multiple Myeloma • Oncology

2seventy bio to Present Data from its Portfolio of Oncology Cell Therapies at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition (Yahoo Finance) - "New pre-clinical data on SC-DARIC33, an investigational, pharmacologically controlled CD33-targeted chimeric antigen receptor (CAR) T cell product, being studied and developed in collaboration with Seattle Children’s Therapeutics for the potential treatment of acute myeloid leukemia (AML), has been accepted for oral presentation. A second oral presentation, in partnership with Bristol Myers Squibb (BMS), will feature updated results from the ongoing Phase I CRB-402 study of the B-cell maturation antigen (BCMA)-targeted CAR T cell therapy bb21217 in patients with relapsed and refractory multiple myeloma (RRMM)."

P1 data • Preclinical • Hematological Malignancies • Multiple Myeloma • Oncology

PLAT-08: A Study Of SC-DARIC33 In Pediatric And Young Adults With Relapsed Or Refractory CD33+ AML (clinicaltrials.gov) - P1; N=18; Not yet recruiting; Sponsor: Seattle Children's Hospital

Clinical • New P1 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • CD33