Work

TCRα/ß Depleted Mobilized Pbscs without Calcineurin Inhibitors in Patients with Fanconi Anemia

Year: 2025

Type: article

Abstract: Background We performed a single center phase II prospective clinical trial (NCT03579875) to test the hypothesis that TCRα/ß depletion would sufficiently deplete GVHD causing α/ß T cells to eliminate the need for prolonged immunosuppression after PBSC transplantation in patients with FA. Methods Patients received conditioning regimen (MacMillan, Blood 2015) with fludarabine , cyclophosphamide and methylprednisolone alone if the patient had marrow failure only and an HLA matched sibling donor (n=2), or with total body irradiation with thymic shielding (n=12) or busulfan (n=17) if there was clonal disease, or if a haploidentical related or HLA matched or mismatched unrelated donor. All but the first patient received one dose of rituximab on day-1 for B cell depletion. Mycophenolate mofetil was given after transplant if the TCRα/ß dose ≥2 × 10 5 TCR α/β T cells/kg recipient (n=4). Mass cytometry (CyTOF) studies included targeting markers for delineating naïve, effector and effector memory CD4 cells and naïve, stem memory, central memory and effector memory CD8 cells, as well as T regulatory, B and γδ T cell subpopulations . Results 31 patients with FA, median 9.5 years (range 1.7-43.8) were enrolled. Patients had marrow failure (n=18), MDS (n=4), relapsed MDS (n=1), APML (n=1), ALL (n=1), immune deficiency (n=1), BRCA2 with clonal abnormality (n=2) or pre-emptively for BRCA2 (n=3), with 2 patients having had a prior transplant . Neutrophil engraftment occurred in all patients, median 9 days (Figure A). Platelet recovery occurred in 30 patients, median 15 days. To date, 3 patients developed grade II-IV acute GVHD . No patient has developed chronic GVHD requiring systemic therapy (Figure B). Probability of survival at 2 years is 90%, including 5/6 BRCA2 patients and all 7 adult patients (Figure C). By 1 year, only 6 patients developed viral infections requiring systemic therapy. Immune recovery in 15 patients was compared to 10 historical FA patients similarly transplanted except for GVHD prophylaxis (TCD by CD34+ selection with calcineurin inhibitor , CNI). Significant finding were: lower proportions of total CD4+ cells (43.0% vs 76.7%, p <0.0002), and memory Tregs (4.8% vs 14.6%, p<0.01), and higher proportions of γδ T cells (30.8% vs 4.8%, p<0.0003) in recipients of TCRα/ß PBSC at day 28. Analysis of γδ T cell proportions at 6 months (16.2% vs 3.2%, p=0.0106; TCRa/bPBSC vs. CD34 selection) indicated that TCRα/ß depletion resulted in a lasting immune imprint, underpinning the differences in reconstitution between these two transplant methodologies (Figure D). Conclusions TCRα/ß depleted PBSC transplantation without CNI results in excellent engraftment , minimal GVHD , few viral infections and excellent survival in FA patients with promising outcomes in those with hematologic malignancy , biallelic BRCA2 genotype and older age who historically often did poorly.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.jtct.2025.01.102