Abstract

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for hematological malignancies and non-malignant disorders. Rapid immune reconstitution (IR) following allogeneic HCT has been shown to be associated with improved clinical outcomes and lower infection rates. A global phase 3 trial (NCT02730299) of omidubicel, an advanced cell therapy manufactured from an appropriately human leukocyte antigen-matched single umbilical cord blood (UCB) unit, showed faster hematopoietic recovery, reduced rates of infection, and shorter hospitalizations in patients randomized to omidubicel compared with those randomized to standard UCB.This optional, prospective substudy of the phase 3 trial characterized the IR kinetics following HCT with omidubicel compared with UCB in a systematic and detailed manner.In this substudy, 37 patients from 14 global sites were included (omidubicel: n=17, UCB: n=20). Peripheral blood samples were collected over 10 predefined time points from 7 to 365 days post-HCT. Flow cytometry immunophenotyping, T cell receptor excision circle quantification, and T cell receptor sequencing were employed to evaluate the longitudinal IR kinetics post-transplant and their association with clinical outcomes.Patient characteristics in the two comparator cohorts were overall statistically similar, except for age and total body irradiation (TBI) based conditioning regimens. The median age (range) for patients who received omidubicel or UCB was 30 (13-62) years and 43 (19-55) years, respectively. The percentages of patients receiving TBI based conditioning regimens were 47% and 70% for omidubicel and UCB recipients, respectively. Graft characteristics differed in their cellular composition. Omidubicel recipients received a 33-fold higher median dose of CD34+ stem cells, while receiving one third of the median CD3+ lymphocyte dose infused to UCB transplanted patients. Compared with UCB, omidubicel recipients exhibited faster IR of all measured lymphoid and myelomonocytic subpopulations, predominantly in the first 14 days post-transplant. This effect involved circulating natural killer (NK) cells, helper T cells, monocytes, and dendritic cells, with superior long-term B cell recovery from Day 28. One-week post-HCT, omidubicel recipients exhibited 4.1 and 7.7 -fold increases in the median helper T and NK cell counts respectively, compared to their UCB transplanted counterparts. By three weeks post-HCT, omidubicel transplanted patients were 3-fold more likely to achieve clinically relevant helper T and NK cell counts of 100 cells/ µL or above. Similar to UCB, omidubicel yielded a balanced cellular subpopulation composition and diverse T cell receptor repertoire in the short to long term. Omidubicel's CD34+ cell content correlated with faster IR by Day 7 post-HCT, which in turn coincided with earlier hematopoietic recovery. Lastly, early NK and helper T cell reconstitution correlated with a decreased rate of post-HCT viral infections, suggesting a plausible explanation for this phenomenon among omidubicel recipients in the phase 3 study.Our findings suggest that omidubicel efficiently promotes IR across multiple immune cells, including CD4+ T cells, B cells, NK cells, and dendritic cell subtypes as early as 7 days post-transplant, potentially endowing recipients of omidubicel with early protective immunity.

View details for DOI 10.1016/j.jtct.2023.04.018

View details for PubMedID 37120136