Phase I, Dose Escalation Study of Naïve T-Cell Depleted Donor Lymphocyte Infusion Following Allogeneic Stem Cell Transplantation

Maung, Ko Ko; Chen, Benny J.; Rizzieri, David A.; Gasparetto, Cristina; Sullivan, Keith M.; Long, Gwynn D.; Engemann, Ashley Morris; Waters‐Pick, Barbara; Nichols, Krista Rowe; Lopez, Richard D.; Kang, Yubin; Sarantopoulos, Stefanie; Sung, Anthony D.; Chao, Nelson J.; Horwitz, Mitchell E.

doi:10.1016/j.bbmt.2018.12.254

Cited by 3 publications

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“…A single‐arm experience with a limited number of patients (n = 35) showed that the incidence of grade II‐IV aGvHD was up to 66% in a MRD cohort, which was not reduced as expected, but the incidence of chronic GvHD was only 9% 27 . However, another phase I dose escalation study found that the maximum administered cell dose of 1 × 10 7 CD3+ cells/kg DLI depleted of CD45RA+ Tn cells did not result in clinically significant acute GvHD in patients following HLA‐identical HSCT 28 . More recently, selective CD45RA T‐cell depletion has been proven to reduce viremia and enhance early T‐cell recovery compared to CD3‐depleted T cells in haploidentical cohorts.…”

Section: To Optimize Graft Composition By Graft Engineeringmentioning

confidence: 84%

Optimizing Allogeneic Grafts in Hematopoietic Stem Cell Transplantation

Huang

2021

Stem Cells Translational Medicine

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely used in the treatment of hematological diseases. It is well known that allogeneic grafts play a key role in predicting transplantation prognosis. Hematopoietic stem cells (HSCs) are a functional part of grafts and are capable of reconstructing hematopoiesis and immunity, but purified HSCs have not been identified or isolated to date. In clinical practice, allogeneic grafts have been optimized to improve transplantation outcomes. The optimized grafts are considered to engraft successfully, reconstruct immunity rapidly, and exert a graft-vs-leukemia (GVL) effect without causing severe graft-vs-host disease (GvHD). In the last several decades, considerable efforts have been made in searching for optimized grafts based on different graft manipulation approaches and different graft sources. Currently, there is no uniform standard for optimized grafts in allogeneic transplantation. In the future, sorting out the cellular elements responsible for the effects of allo-HSCT might be a research direction for further optimization of grafts. In this review, we propose the concept of optimized grafts and summarize the recent advances made in the process of optimizing grafts.

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Section: To Optimize Graft Composition By Graft Engineeringmentioning

confidence: 84%

Optimizing Allogeneic Grafts in Hematopoietic Stem Cell Transplantation

Huang

2021

Stem Cells Translational Medicine

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“…In our case, the depletion was very efficient and CD45RA was undetectable. Recently, there had been published phase 1 dose escalation study result on CD45RA depleted DLI, with maximum cell dose set at 1 × 10 7 /kg, 27 which was the cell dose administered to our patient in the 2 DLIs.…”

Section: Controversy On Cell Dose and Dosing Interval Of Cd45ra-depleted DLI And Use Of Atg Prior To Dlimentioning

confidence: 99%

Repeated CD45RA‐depleted DLI successfully increases donor chimerism in a patient with beta‐thalassemia major after haploidentical stem cell transplant

Chan

Kwok

Chiang

et al. 2020

Pediatric Transplantation

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Allogeneic hematopoietic stem cell transplantation is curative for transfusiondependent thalassemia, but mixed chimerism (MC) may herald graft rejection. We report a child who failed bone marrow transplant (BMT) from matched unrelated donor (MUD) successfully salvaged with haploidentical peripheral blood stem cell transplant (PBSCT), but had MC in T-lymphocyte compartment despite near-complete donor chimerism in myeloid compartment. MC was successfully improved by repeated CD45RA-depleted donor lymphocyte infusion (DLI). A 2-year-old Chinese girl with beta-thalassemia major underwent 12/12-MUD BMT with HU/AZA/Cy/Flu/ Bu/TT conditioning resulted in graft rejection. As donor refused second donation, rescue haploidentical PBSCT was performed with alemtuzumab/fludarabine/treosulfan conditioning. Harvest product was CD3/CD45RA depleted with extra products cryopreserved. Split cell chimerism performed 1-month after haplo-transplant showed 97% mother, 3% MUD, and 0% host for granulocytes but 38% mother, 62% MUD, and 0% host for CD3 + T cells. In view of low haploidentical donor chimerism in T-lymphocyte compartment, CD45RA-depleted DLI using cryopreserved product was performed on day + 38, after thymoglobulin 3 mg/kg given as T-cell depletion 3 days beforehand. T-cell chimerism improved to 51% mother and 49% MUD post-DLI. Second cryopreserved CD45RA-depleted DLI was given 17 days after the first DLI (day + 55), and 100% full chimerism of mother's T cells was gradually established without significant graft-versus-host disease (GVHD) or viral reactivation. To con-How to cite this article: Chan WYK, Kwok JSY, Chiang AKS, et al. Repeated CD45RA-depleted DLI successfully increases donor chimerism in a patient with beta-thalassemia major after haploidentical stem cell transplant. Pediatr Transplant.

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“…Furthermore, low immunogenicity of some T-cell epitopes (e.g., Epstein-Barr nuclear antigen 1, EBNA1) also causes problems [19]. Consequently, strategies to refine DLIs through selective T N depletion were developed to obtain antiviral memory T-cell products with the potential to protect patients from viral infection/reactivation while reducing the risk of GvHD occurrence [20-22].…”

Section: Introductionmentioning

confidence: 99%

Variances in Antiviral Memory T-Cell Repertoire of CD45RA- and CD62L-Depleted Lymphocyte Products Reflect the Need of Individual T-Cell Selection Strategies to Reduce the Risk of GvHD while Preserving Antiviral Immunity in Adoptive T-Cell Therapy

Mangare

Tischer-Zimmermann

Bonifacius

et al. 2021

Transfus Med Hemother

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Introduction: Viral infections and reactivations still remain a cause of morbidity and mortality after hematopoietic stem cell transplantation due to immunodeficiency and immunosuppression. Transfer of unmanipulated donor-derived lymphocytes (DLI) represents a promising strategy for improving cellular immunity but carries the risk of graft versus host disease (GvHD). Depleting alloreactive naïve T cells (TN) from DLIs was implemented to reduce the risk of GvHD induction while preserving antiviral memory T-cell activity. Here, we compared two TN depletion strategies via CD45RA and CD62L expression and investigated the presence of antiviral memory T cells against human adenovirus (AdV) and Epstein-Barr virus (EBV) in the depleted fractions in relation to their functional and immunophenotypic characteristics. Methods: T-cell responses against ppEBV_EBNA1, ppEBV_Consensus and ppAdV_Hexon within TN-depleted (CD45RA−/CD62L−) and TN-enriched (CD45RA+/CD62L+) fractions were quantified by interferon-gamma (IFN-γ) ELISpot assay after short- and long-term in vitro stimulation. T-cell frequencies and immunophenotypic composition were assessed in all fractions by flow cytometry. Moreover, alloimmune T-cell responses were evaluated by mixed lymphocyte reaction. Results: According to differences in the phenotype composition, antigen-specific T-cell responses in CD45RA− fraction were up to 2 times higher than those in the CD62L− fraction, with the highest increase (up to 4-fold) observed after 7 days for ppEBV_EBNA1-specific T cells. The CD4+ effector memory T cells (TEM) were mainly responsible for EBV_EBNA1- and AdV_Hexon-specific T-cell responses, whereas the main functionally active T cells against ppEBV_Consensus were CD8+ central memory T cells (TCM) and TEM. Moreover, comparison of both depletion strategies indicated that alloreactivity in CD45RA− was lower than that in CD62L− fraction. Conclusion: Taken together, our results indicate that CD45RA depletion is a more suitable strategy for generating TN-depleted products consisting of memory T cells against ppEBV_EBNA1 and ppAdV_Hexon than CD62L in terms of depletion effectiveness, T-cell functionality and alloreactivity. To maximally exploit the beneficial effects mediated by antiviral memory T cells in TN-depleted products, depletion methods should be selected individually according to phenotype composition and CD4/CD8 antigen restriction. TN-depleted DLIs may improve the clinical outcome in terms of infections, GvHD, and disease relapse if selection of pathogen-specific donor T cells is not available.

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Phase I, Dose Escalation Study of Naïve T-Cell Depleted Donor Lymphocyte Infusion Following Allogeneic Stem Cell Transplantation

Cited by 3 publications

References 0 publications

Optimizing Allogeneic Grafts in Hematopoietic Stem Cell Transplantation

Optimizing Allogeneic Grafts in Hematopoietic Stem Cell Transplantation

Repeated CD45RA‐depleted DLI successfully increases donor chimerism in a patient with beta‐thalassemia major after haploidentical stem cell transplant

Variances in Antiviral Memory T-Cell Repertoire of CD45RA- and CD62L-Depleted Lymphocyte Products Reflect the Need of Individual T-Cell Selection Strategies to Reduce the Risk of GvHD while Preserving Antiviral Immunity in Adoptive T-Cell Therapy

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