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483 Trem-Cel, a CRISPR/Cas9 Gene-Edited Allograft Lacking CD33, Shows Rapid Primary Engraftment with CD33-Negative Hematopoiesis in Patients with High-Risk Acute Myeloid Leukemia (AML) and Avoids Hematopoietic Toxicity during Gemtuzumab Ozogamicin (GO) Maintenance Post-Hematopoietic Cell Transplant (HCT)Clinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 801. Gene Therapies: New Approaches From Bench to Bedside
Hematology Disease Topics & Pathways:
Research, clinical trials, Acute Myeloid Malignancies, AML, Biological therapies, Antibody Therapy, adult, Clinical Research, drug development, Diseases, Gene Therapy, Therapies, Myeloid Malignancies, Monoclonal Antibody Therapy, Technology and Procedures, gene editing, Study Population, Human, Minimal Residual Disease
Sunday, December 10, 2023: 10:00 AM

John DiPersio1, Brenda W Cooper, MD2, Hyung C Suh, MD/PhD3, Divya Koura, MD4, Lea Bernard, MD5, Nirali N. Shah, M.D.6, Roland B. Walter, MD, PhD, MS7, Miguel-Angel Perales, MD8, Markus Mapara, MD9, Roni Tamari, MD8, Michael R. Loken, PhD10*, Kyle Breitschwerdt11*, Sritama Nath, PhD11*, Glen D Raffel, MD12 and Guenther Koehne, MD, PhD13

1Division of Oncology, Washington University School of Medicine, Saint Louis, MO
2University Hospitals Seidman Cancer Center, Cleveland, OH
3Stem Cell Transplantation and Cellular Therapy Program, John Theurer Cancer Center, Hackensack Meridian Health, Hackensack, NJ
4UCSD Moores Cancer Center, La Jolla, CA
5Maisonneuve-Rosemont Hospital, Montreal, QC, CAN
6Pediatric Oncology Branch, National Institutes of Health, Bethesda, MD
7Translational Science and Therapeutics Division, Fred Hutchinson Cancer Research Center, Seattle, WA
8Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
9Blood and Marrow Stem Cell Transplantation Program, Division of Hematology & Oncology, Columbia University Irving Medical Center, New York, NY
10Hematologics, Inc., Seattle, WA
11Vor Biopharma, Cambridge, MA
12Vor Biopharma, Waban, MA
13Baptist Health South Florida, Miami Cancer Institute, Miami, FL

Background: Allogeneic HCT is the standard of care for eligible patients with AML harboring high-risk features such as adverse-risk cytogenetics or measurable residual disease (MRD), however, the majority of these patients still relapse post-HCT and have very poor outcomes. The use of maintenance therapies intended to control post-HCT relapse is often limited by hematopoietic toxicity towards normal engrafted cells. GO (tradename: MylotargTM) is an anti-CD33 antibody-drug conjugate targeting CD33+ AML, but its use is limited by on-target, off-tumor hematopoietic toxicity toward CD33+ myeloid and progenitor cells. Tremtelectogene empogeditemcel (trem-cel; formerly VOR33) is a hematopoietic stem and progenitor cell product, manufactured from CD34+ cells isolated from a patient-matched donor, that has been modified by CRISPR/Cas9 gene-editing to lack CD33. Trem-cel was developed to protect normal hematopoietic cells from post-HCT CD33-directed therapies and allow exclusive targeting of residual leukemia.

Methods: VBP101(NCT04849910) is a first-in-human Phase 1/2 open-label multicenter trial to establish the safety of using trem-cel as a donor allograft for CD33+ AML patients who are at high risk of relapse and undergoing myeloablative HCT followed by treatment with GO. Eligible patients (18-70 y) must have CD33+ AML with high-risk features for relapse, such as adverse-risk cytogenetics or MRD, and a 10/10 human leukocyte antigen (HLA)-matched related or unrelated donor. Donors undergo mobilization with G-CSF and plerixafor prior to apheresis. Trem-cel is manufactured from isolated CD34+ cells and cryopreserved. Patients undergo either a busulfan- or TBI-based myeloablative conditioning regimen prior to transplantation with trem-cel. After engraftment and recovery of a sufficient CD33-negative neutrophil count, patients begin maintenance therapy with GO in a 3+3 dose escalation strategy starting at 0.5 mg/m2 every 28d for 4-8 cycles.

Results: To date, 6 patients between 32-68 y (median 63.5 y) have been treated with trem-cel at a median dose of 5.2 x 106 CD34+ cells/kg (2.6 - 7.6) and CD33 editing efficiency of 88% (80 – 91). Primary neutrophil engraftment occurred in all patients after a median of 10 days (9 – 11) and platelet recovery occurred after a median of 16 days (15-22) excluding one patient with documented anti-platelet antibody (Fig 1). At the day 28 assessment, full peripheral blood (PB) myeloid chimerism was achieved in all patients and CD33 expression by flow was absent in a median of 94% of neutrophils (86–99) and 92% of monocytes (82 - 94), respectively. Comparable CD33 edits were detected in donor cells across myeloid and lymphoid lineages. GO dosing is ongoing at 0.5 mg/m2 dose and neutrophil and platelet counts remain stable, suggesting protection from GO-mediated hematotoxicity. Following the 0.5 mg/ m2 dose, the exposures of GO were predictively higher in the context of CD33-negative hematopoiesis relative to GO doses of 1–2 mg/m2 (Cmax) and 4–5 mg/m2 (AUC), respectively, in CD33+ relapsed/refractory AML patients. During GO dosing, the percent of CD33-negative cells increased in the PB and bone marrow (BM) across cell lineages consistent with enrichment of edited donor cells. Patients are followed for safety, hematologic protection from GO, disease status, and persistence of CD33 editing.

Disclosures: DiPersio: Magenta: Current holder of stock options in a privately-held company, Other: Ownership Investment, Patents & Royalties; Vertex: Consultancy; Macrogenics: Research Funding; Bioline: Consultancy; Rivervest: Consultancy; WUGEN: Current holder of stock options in a privately-held company, Other: Ownership Investment, Patents & Royalties, Research Funding. Suh: Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Koura: BMS: Consultancy, Research Funding. Shah: CARGO: Consultancy; VOR: Consultancy, Research Funding; Immunoadoptive Cell Therapy Private Limited: Consultancy, Other: Scientific Advisory Board; Lentigen: Research Funding. Walter: Amgen, Aptevo, Celgene, Janssen, Jazz, MacroGenics, Pfizer: Research Funding; ImmunoGen, Jura: Consultancy, Research Funding; Abbvie, Adicet, Amphivena, BerGenBio, Bristol Myers Squibb, GlaxoSmithKline, Orum: Consultancy. Perales: Karyopharm: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Exevir: Consultancy, Honoraria; Cidara Therapeutics: Consultancy, Other; Astellas: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Nektar Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; Medigene: Consultancy, Other; Syncopation: Honoraria; Sellas Life Sciences: Consultancy; NexImmune: Consultancy, Current equity holder in publicly-traded company; Servier: Other; Miltenyi Biotec: Honoraria; Caribou: Consultancy, Honoraria; Kite: Consultancy, Honoraria, Research Funding; Equillium: Consultancy, Honoraria; DSMB: Other; Vor Biopharma: Consultancy, Honoraria; Adicet: Honoraria; Celgene: Honoraria; Allogene: Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Omeros: Consultancy, Current equity holder in publicly-traded company, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; VectivBio AG: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Allovir: Consultancy; Orcabio: Consultancy, Current equity holder in publicly-traded company, Honoraria; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding. Mapara: Crispr/vertex: Consultancy; Incyte: Consultancy; Bluebird bio: Consultancy. Loken: Hematologics, Inc.: Current Employment, Current equity holder in private company. Breitschwerdt: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Nath: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Raffel: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company.

*signifies non-member of ASH