tremtelectogene empogeditemcel (VOR33)

P1/2, N=24, Recruiting, Vor Biopharma | N=18 --> 24 | Trial completion date: Sep 2025 --> Jan 2027 | Trial primary completion date: Dec 2023 --> Feb 2025

P=N/A, N=36, Recruiting, Vor Biopharma | Trial completion date: Nov 2038 --> Jan 2040 | Trial primary completion date: Nov 2038 --> Jan 2040

Trem-cel (formerly VOR33) is manufactured from CD34+ cells isolated from matched-donor apheresis and modified by CRISPR/Cas9 gene-editing to remove CD33, with the goal of protecting normal hematopoietic cells from post-HCT CD33-directed therapies...Donors undergo mobilization with G-CSF and plerixafor prior to apheresis and manufacturing of trem-cel... Initial results demonstrate trem-cel has rapid primary neutrophil engraftment similar to non-edited CD34-selected grafts (Luznik et al 2022, JCO 40:356-368) and a high CD33 editing efficiency leading to a majority of myeloid cells lacking CD33 expression and supporting the biologic dispensability of CD33. The exposure at 0.5mg/m2 GO dose corresponded to higher doses of GO in AML patients, possibly due to reduction of the CD33 hematopoietic antigen sink. Minimal cytopenias have been observed thus far after treatment with GO, supporting the hypothesis that CD33 deletion can protect donor cells from CD33-targeted therapies.

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...Donors undergo mobilization with G-CSF and plerixafor prior to apheresis...Patients undergo either a busulfan- or TBI-based myeloablative conditioning regimen prior to transplantation with trem-cel... 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.

P1/2, N=18, Recruiting, Vor Biopharma | Trial primary completion date: May 2023 --> Dec 2023

Clinical Trial Registry : NCT04849910 Background: In order to reduce AML relapse post-HCT, a CD33 CRISPR/Cas9 gene-edited donor allograft, tremtelectogene empogeditemcel (trem-cel), formerly VOR33, was developed to enable post-HCT CD33-directed therapies while protecting healthy donor cells from on-target myelosuppression... A 64 y-old F patient with relapsed CD33+ TP53 mutant AML, adverse cytogenetics, and CRi with measurable residual disease (MRD; 1.8% bone marrow [BM] blasts), underwent myeloablative busulfan/melphalan/fludarabine/ATG conditioning followed by HCT with trem-cel. Trem-cel was manufactured from G-CSF + plerixafor-mobilized cells from an HLA-matched (10/10) unrelated donor and was composed of 7.6 x 106 CD34+ cells/kg with 88% CD33 deletion... This is the first report of successful engraftment of a CD33-edited allogeneic donor graft and toleration of post-HCT GO. Engraftment was comparable to similarly treated patients who received non-edited CD34-selected grafts (median 11 days) (Luznik et al 2022, JCO 40:356-368). Consistent with high CD33 editing efficiency in trem-cel, the majority of PB and BM myeloid cells lacked CD33 expression.

Background: In order to reduce AML relapse post-HCT, a CD33 CRISPR/Cas9 gene-edited donor allograft, tremtelectogene empogeditemcel (trem-cel), formerly VOR33, was developed to enable post-HCT CD33-directed therapies while protecting healthy donor cells from on-target myelosuppression... A 64 y-old F patient with relapsed CD33 + TP53 mutant AML, adverse cytogenetics, and CRi with measurable residual disease (MRD; 1.8% bone marrow [BM] blasts), underwent myeloablative busulfan/melphalan/fludarabine/ATG conditioning followed by HCT with trem-cel. Trem-cel was manufactured from G-CSF + plerixafor-mobilized cells from an HLA-matched (10/10) unrelated donor and was composed of 7.6 x 10 6 CD34 + cells/kg with 88% CD33 deletion... This is the first report of successful engraftment of a CD33-edited allogeneic donor graft and toleration of post-HCT GO. Engraftment was comparable to similarly treated patients who received non-edited CD34-selected grafts (median 11 days) (Luznik et al 2022, JCO 40:356-368). Consistent with high CD33 editing efficiency in trem-cel, the majority of PB and BM myeloid cells lacked CD33 expression.

Key exclusion criteria include prior auto/allo-HCT or prior treatment with GO.Related and unrelated donors undergo mobilization with G-CSF and plerixafor prior to cell collection...Subjects undergo either a busulfan- or TBI-based myeloablative conditioning regimen prior to transplantation with VOR33...A Dose Escalation Committee and Data Safety Monitoring Committee will review GO dosing levels and monitor overall trial safety, respectively. VBP101 is currently open for enrollment and recruiting patients.

P=N/A, N=36, Recruiting, Vor Biopharma | Not yet recruiting --> Recruiting

P=N/A, N=36, Not yet recruiting, Vor Biopharma

Genetic ablation of CD33 using CRISPR/Cas9 engineering of the hematopoietic stem cell (HSC) transplant (VOR33) represents a synthetic biology approach to generating a leukemia-specific antigen in the transplant recipient. Non-transduced T cells in the mob-CAR T-cell population showed limited ‘bystander’ activation, indicating a potentially favorable clinical toxicity profile. Additional in vivo assessment of mob-CAR T-cell function shows effective tumor clearance, which supports further efforts towards their clinical use in combination with engineered HSCs for the treatment of AML patients.

P1/2, N=18, Recruiting, Vor Biopharma | Enrolling by invitation --> Recruiting

P1/2, N=18, Enrolling by invitation, Vor Biopharma | Not yet recruiting --> Enrolling by invitation | Initiation date: Apr 2021 --> Aug 2021

P1/2, N=18, Not yet recruiting, Vor Biopharma