Phase I dose escalation study of naive T-cell depleted donor lymphocyte infusion following allogeneic stem cell transplantation

Maung, Ko Ko; Chen, Benny J.; Li, Zhiguo; 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:10.1038/s41409-020-0991-5

Cited by 24 publications

(12 citation statements)

References 16 publications

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“…Inspired by the preclinical studies which indicated that naïve T cells are major drivers of GVHD, a phase I dose escalating study of CD45RA + naïve T cell-depleted DLI was conducted in allo-HCT patients. Among the 28 patients evaluated, no patient developed grade III/IV acute GVHD or severe cGVHD, indicating the preventive capacity of this technique against GVHD (126). Moreover, since dendritic cells may bolster T cell responses through antigen presentation, a phase I trial has evaluated the co-infusion of DC followed by DLI in 16 relapsed patients with hematological malignancies after allo-HCT.…”

Section: Other Techniques Of DLI Composition Manipulation and Engineeringmentioning

confidence: 99%

Optimization of Donor Lymphocyte Infusion for AML Relapse After Allo-HCT in the Era of New Drugs and Cell Engineering

Yang

Yuan

et al. 2022

Front. Oncol.

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Donor lymphocyte infusion (DLI) is a key strategy for the treatment of AML relapse after allogeneic hematopoietic cell transplantation (allo-HCT) and has been used for either prophylactic, pre-emptive, or therapeutic purposes. However, the prognosis of these patients remains dismal even after DLI infusion (2-year overall survival, ~25%), and the efficacy is achieved at the cost of toxicities such as graft-versus-host (GVH) disease. Attempts to optimize DLI efficacy and safety, such as dose/timing modification and the use of cytoreduction, before DLI have been performed previously. Recently, a great number of novel targeted and immunomodulatory agents have emerged. Some of them, such as hypomethylating agents, FLT3 and Bcl-2 inhibitors, have been used in combination with DLI, aiming to enhance the graft-versus-leukemia effect. Moreover, manipulation of the DLI graft through cell selection (e.g., donor NK cells) or cell engineering (donor CAR-T cells) has shown potentially superior anti-tumor effects but less GVH effect than conventional DLI in clinical trials. This review summarizes the recent advances on the use of DLI for the prophylaxis/treatment of AML relapse and discusses future strategies which may further improve the treatment efficacy.

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Section: Other Techniques Of DLI Composition Manipulation and Engineeringmentioning

confidence: 99%

Optimization of Donor Lymphocyte Infusion for AML Relapse After Allo-HCT in the Era of New Drugs and Cell Engineering

Yang

Yuan

et al. 2022

Front. Oncol.

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“…Two recent phase I studies have transitioned this work to investigate naïve T cell depleted or CD8 + memory T cells for donor-lymphocyte infusions (DLI) respectively ( 38 , 39 ). Both of these studies showed that DLI infusions with their respective T cell populations were safe, feasible and were associated with a low incidence of acute GVHD (aGVHD).…”

Section: The Tcr : Mhc Interaction: Signalmentioning

confidence: 99%

GVHD Pathogenesis, Prevention and Treatment: Lessons From Humanized Mouse Transplant Models

2021

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Graft-vs-host disease (GVHD) is the most common cause of non-relapse mortality following allogeneic hematopoietic stem cell transplantation (HSCT) despite advances in conditioning regimens, HLA genotyping and immune suppression. While murine studies have yielded important insights into the cellular responses of GVHD, differences between murine and human biology has hindered the translation of novel therapies into the clinic. Recently, the field has expanded the ability to investigate primary human T cell responses through the transplantation of human T cells into immunodeficient mice. These xenogeneic HSCT models benefit from the human T cell receptors, CD4 and CD8 proteins having cross-reactivity to murine MHC in addition to several cytokines and co-stimulatory proteins. This has allowed for the direct assessment of key factors in GVHD pathogenesis to be investigated prior to entering clinical trials. In this review, we will summarize the current state of clinical GVHD research and discuss how xenogeneic HSCT models will aid in advancing the current pipeline of novel GVHD prophylaxis therapies into the clinic.

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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: Discussionmentioning

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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Phase I dose escalation study of naive T-cell depleted donor lymphocyte infusion following allogeneic stem cell transplantation

Cited by 24 publications

References 16 publications

Optimization of Donor Lymphocyte Infusion for AML Relapse After Allo-HCT in the Era of New Drugs and Cell Engineering

Optimization of Donor Lymphocyte Infusion for AML Relapse After Allo-HCT in the Era of New Drugs and Cell Engineering

GVHD Pathogenesis, Prevention and Treatment: Lessons From Humanized Mouse Transplant Models

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

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