Genome-Edited HCT Clinical Trial Demonstrates Engraftment in First Patient With AML


The patient tolerated administration of Mylotarg after engraftment.

Vor Bio’s tremtelectogene empogeditemcel (trem-cel; VOR33), an investigational allogeneic genome-edited hematopoietic stem and progenitor cell product, has demonstrated successful transplant and engraftment in the first patient with acute myeloid leukemia (AML) in the phase 1/2a VBP101 clinical trial (NCT04849910).

Trem-cel consists of related or unrelated donor cells that have been modified with CRISPR/Cas9 editing for the deletion of CD33 protein. It is intended to allow for continued use of CD33-targeted therapies, such as Mylotarg or CD33-targeted chimeric antigen receptor T-cell (CAR-T) therapy, after transplant. The patient in the trial received a dose of 7.6x106 CD34+ viable cells/kg, manufactured with a CD33 editing efficiency of 88%, after myeloablative conditioning. Neutrophil engraftment was achieved at 10 days after the transplant and platelet recovery occurred at 22 days. More than 90% of the patient's peripheral blood cells were determined to lack CD33, and the patient exhibited 100% donor chimerism. No infusion reactions were reported. After engraftment, the patient was administered 0.5 mg/m2 of Mylotarg, which was tolerated with no treatment-related adverse events (AEs), liver enzyme changes, or negative effects on neutrophil or platelet counts reported in the 20 days after administration.

“The unmet medical need for AML is significant and hematopoietic cell transplant (HCT) is the best hope for these patients,” Brenda Cooper, MD, professor of Medicine in the Cellar Therapy Program at University Hospitals, Seidman Cancer Center, and an investigator on the VBP101 study, said in a statement regarding the news. “Early treatment data in the first patient show that trem-cel can engraft normally and maintain normal hematopoiesis following Mylotarg dosing, which typically causes severe cytopenias. These data support the promise of this approach.”

The open-label, multicenter VBP101 study is expected to enroll 18 patients aged 18 to 70 years who have a confirmed diagnosis of AML in the first or second complete remission (CR) or have bone marrow blasts of 10% or less without circulating blasts. Participants are required to have an AML sample that shows evidence of CD33 expression. Participants are additionally required to have AML with intermediate or high-risk disease-related genetics and the presence of minimal residual disease (patients in their second CR or who have persistent morphologic blasts may have favorable disease-related genetics); a candidate for HLA-matched allogeneic HCT using a myeloablative conditioning regimen; a related or unrelated stem cell donor that is a 10/10 match for HLA-A, -B, -C, -DRB1 and –DQB1; a Karnofsky score of at least 70; a left ventricular ejection fraction of at least 50%; a diffusing capacity of lung for carbon monoxide, forced vital capacity, and forced expiratory volume in 1 second of at least 66%; an estimated glomerular filtration rate of at least 60 mL/min; and a total bilirubin of less than 1.5x upper limit of normal (ULN) (or if ≥1.5× ULN direct bilirubin <ULN and ALT/AST <1.5× ULN). Patients who have disease-related genetics t(15; 17)(q22; q21), or t(9; 22)(q34; q11), or other evidence of acute promyelocytic leukemia or chronic myeloid leukemia; patients who were previously treated with Mylotarg; patients with active central nervous system leukemia or a history of other active malignancy; patients with Gilbert’s syndrome; and patients who previously received stem cell transplantation will be excluded from the study. Additional exclusion criteria relates to infection history.

The trial’s primary end point is the incidence of neutrophil engraftment, defined as the first day of 3 consecutive days of absolute neutrophil count of at least 500 cells/mm2 by 28 days. Secondary end points include time to neutrophil engraftment, time to platelet recovery, incidence of acute graft versus host disease (GVHD) grade (G) G2-G4 and G3-G4, incidence of chronic GVHD, incidence of primary and secondary graft failure, incidence of toxicities, incidence of transplant-related mortality, percentage of CD33-negative myeloid cells, relapse-free survival, and overall survival. The study is recruiting at locations in the United States and Canada and is estimated to be completed in September 2025.

“These early engraftment data represent the first time genome engineering has been used to genetically alter donor cells by removing an antigen present on blood cells, thereby allowing treatment using a CD33 targeted therapy while protecting normal blood cells,” Robert Ang, president and chief executive officer, Vor Bio, added to the statement. “These encouraging data represent the first clinical validation of our platform to potentially enable next-generation transplants for patients with blood cancers. We look forward to sharing additional data updates in 2023.” CGTLive previously spoke with Ang about trem-cel's development in an interview last year.

First AML patient successfully transplanted with Vor Bio’s investigational trem-cel (VOR33) and tolerated mylotarg. News release. Vor Bio. December 7, 2022. 
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