P1396: CD33-DELETED HEMATOPOIETIC STEM AND PROGENITOR CELLS DISPLAY NORMAL ENGRAFTMENT AFTER HEMATOPOIETIC CELL TRANSPLANT (HCT) AND TOLERATE POST-HCT GEMTUZUMAB OZOGAMICIN (GO) WITHOUT CYTOPENIAS

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: 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. Aims: VBP101 (NCT04849910) is a Phase 1/2a trial designed to evaluate the safety of trem-cel and GO (Mylotarg™), an anti-CD33 antibody-drug conjugate, in AML patients who are at a high risk of relapse post-HCT. Methods: Patients with CD33+ AML and prognostic factors for high risk of relapse post-HCT underwent myeloablative busulfan/melphalan/fludarabine/ATG conditioning followed by HCT with trem-cel. Trem-cel was manufactured from G-CSF + plerixafor-mobilized cells from HLA-matched (10/10) unrelated donors. As part of the trial’s initial dose escalation, patients are treated with up to four 28-day cycles of GO, with cohort 1 starting at 0.5 mg/m2 on the first day of each cycle, beginning at ~60 days post-HCT with trem-cel. Results: To date, three patients underwent HCT with trem-cel and received cell doses between 3 and 8 x 106 CD34+ cells/kg with 80% to 88% CD33 deletion. For all three patients, neutrophil engraftment occurred on days 10–11 (Fig. 1a). Patient 1 showed 100% donor chimerism in whole blood and myeloid cells at D28 up to the end of the study (D147). At the D28 assessment, 95% of neutrophils and 94% of monocytes in peripheral blood (PB) were CD33 negative. Similarly, bone marrow (BM) analysis showed 95% of maturing myeloid cells, 92% of maturing monocytes and 94% of CD34+ myeloblasts were CD33 negative with development patterns comparable to a reference non-edited post-HCT BM. Similar levels of CD33 negativity were observed at the D28 assessment in the PB and BM of patient 2. Patient 1 was treated with a single infusion of 0.5 mg/m2 of GO at each of the 28-day cycles for a total of 3 cycles. PK analysis during the first cycle of GO demonstrated a Cmax of 259 ng/mL and AUCinf of 22924 ng/mL*hr, which was comparable to doses of 1–2 mg/m2 and 4–5 mg/m2, respectively in AML patients, exposures predicted to cause cytopenias. CD33-negative donor myeloid hematopoiesis was enriched from 96% to 99.9% following the first dose of GO. This enrichment was reflected at a genetic level, where enrichment of CD33 deletion was observed in both myeloid and lymphoid lineages following the first dose of GO. No significant decrease in neutrophil or platelet counts was observed through the 3 cycles of GO treatment for up to D147 (Fig 1b). Patients 2 & 3 are scheduled to begin GO treatment after D+60. No trem-cel-related adverse events were reported in any of the 3 patients. There was no incidence of elevations in liver function tests after GO or other GO-related SAEs. Summary/Conclusion: CD33-edited allogeneic donor cells were successfully engrafted, with neutrophil engraftment similar to patients who received non-edited CD34-selected grafts (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. The CD33 deletion was detected across donor cells of myeloid and lymphoid lineages, suggesting successful editing of a multipotent progenitor. In the context of a CD33-deleted graft, PK of a 0.5mg/m2 dose of GO demonstrated a higher Cmax and AUC than previously reported in AML patients. No cytopenias were observed after treatment with GO, supporting the hypothesis that CD33 deletion can protect donor cells from GO-mediated toxicity. These initial data support the biologic dispensability of CD33 and a potential approach enabling post-HCT treatment with GO and other CD33-targeted therapies while avoiding typical on-target myelosuppressive toxicity.Keywords: Gemtuzumab ozogamicin, Gene therapy, AML, Allogeneic bone marrow transplant

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