scholarly journals Impact of Common Graft Versus Leukemia Minor Histocompatibility Antigens on the Outcomes of Allogeneic Hematopoietic Cell Transplantation (alloHCT)

2021 ◽  
Vol 27 (3) ◽  
pp. S156-S158
Author(s):  
Hancong Tang ◽  
Kelly Olsen ◽  
Othmane Jadi ◽  
Junke Wang ◽  
Yiwen Wang ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Histocompatibility Antigens ◽  
Minor Histocompatibility Antigens ◽  
Graft Versus Leukemia

scholarly journals A Model of Minor Histocompatibility Antigens in Allogeneic Hematopoietic Cell Transplantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Paul J. Martin ◽  
David M. Levine ◽  
Barry E. Storer ◽  
Xiuwen Zheng ◽  
Deepti Jain ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Open Reading Frames ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Histocompatibility Antigens ◽  
Minor Histocompatibility Antigens ◽  
Graft Versus Host

Minor histocompatibility antigens (mHAg) composed of peptides presented by HLA molecules can cause immune responses involved in graft-versus-host disease (GVHD) and graft-versus-leukemia effects after allogeneic hematopoietic cell transplantation (HCT). The current study was designed to identify individual graft-versus-host genomic mismatches associated with altered risks of acute or chronic GVHD or relapse after HCT between HLA-genotypically identical siblings. Our results demonstrate that in allogeneic HCT between a pair of HLA-identical siblings, a mHAg manifests as a set of peptides originating from annotated proteins and non-annotated open reading frames, which i) are encoded by a group of highly associated recipient genomic mismatches, ii) bind to HLA allotypes in the recipient, and iii) evoke a donor immune response. Attribution of the immune response and consequent clinical outcomes to individual peptide components within this set will likely differ from patient to patient according to their HLA types.

scholarly journals Therapy of relapsed leukemia after allogeneic hematopoietic cell transplantation with T cells specific for minor histocompatibility antigens

Blood ◽  
2010 ◽  
Vol 115 (19) ◽  
pp. 3869-3878 ◽  
Author(s):  
Edus H. Warren ◽  
Nobuharu Fujii ◽  
Yoshiki Akatsuka ◽  
Colette N. Chaney ◽  
Jeffrey K. Mito ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cell Transplantation ◽  
Adoptive Transfer ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Histocompatibility Antigens ◽  
T Cell Therapy ◽  
Minor Histocompatibility Antigens

Abstract The adoptive transfer of donor T cells that recognize recipient minor histocompatibility antigens (mHAgs) is a potential strategy for preventing or treating leukemic relapse after allogeneic hematopoietic cell transplantation (HCT). A total of 7 patients with recurrent leukemia after major histocompatibility complex (MHC)–matched allogeneic HCT were treated with infusions of donor-derived, ex vivo–expanded CD8+ cytotoxic T lymphocyte (CTL) clones specific for tissue-restricted recipient mHAgs. The safety of T-cell therapy, in vivo persistence of transferred CTLs, and disease response were assessed. Molecular characterization of the mHAgs recognized by CTL clones administered to 3 patients was performed to provide insight into the antileukemic activity and safety of T-cell therapy. Pulmonary toxicity of CTL infusion was seen in 3 patients, was severe in 1 patient, and correlated with the level of expression of the mHAg-encoding genes in lung tissue. Adoptively transferred CTLs persisted in the blood up to 21 days after infusion, and 5 patients achieved complete but transient remissions after therapy. The results of these studies illustrate the potential to selectively enhance graft-versus-leukemia activity by the adoptive transfer of mHAg-specific T-cell clones and the challenges for the broad application of this approach in allogeneic HCT. This study has been registered at http://clinicaltrials.gov as NCT00107354.

scholarly journals The Elephant in The Room: AML Relapse Post Allogeneic Hematopoietic Cell Transplantation

2022 ◽  
Vol 11 ◽  
Author(s):  
Iman Abou Dalle ◽  
Ali Atoui ◽  
Ali Bazarbachi
Keyword(s):  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Chemotherapy Regimen ◽  
Current Treatment ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Immune Microenvironment ◽  
Graft Versus Leukemia ◽  
Oncogenic Mutations

Relapsed acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation (allo-HCT) is an unfavorable event associated with a poor prognosis, particularly for patients with early relapses. It usually arises from resistant leukemic blasts that escaped both preparative chemotherapy regimen and the graft-versus-leukemia (GVL) effect. Independent from the choice of salvage treatment, only minority of patients can achieve durable remissions. In recent years, better understanding of the disease relapse biology post allo-HCT allowed the application of newer strategies that could induce higher rates of remission, and potential longer survival. Those strategies aim at optimizing drugs that have a direct anti-leukemia activity by targeting different oncogenic mutations, metabolism pathways or surface antigens, and concurrently enhancing the immune microenvironment to promote GVL effect. This review discusses the current treatment landscape of AML relapse post allo-HCT.

scholarly journals IFN-γ promotes graft-versus-leukemia effects without directly interacting with leukemia cells in mice after allogeneic hematopoietic cell transplantation

Blood ◽  
2011 ◽  
Vol 118 (13) ◽  
pp. 3721-3724 ◽  
Author(s):  
Yanping Yang ◽  
Hui Wang ◽  
Hui Yu ◽  
Beow Yong Yeap ◽  
Tingting Liang ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Bone Marrow Cells ◽  
Direct Interaction ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Leukemia Cells ◽  
Mouse Bone Marrow ◽  
Graft Versus Leukemia ◽  
Ifn Γ

Abstract The ability of IFN-γ to enhance graft-versus-leukemia (GVL) activity without direct interaction with leukemia cells was examined by comparing GVL effects against IFN-γ receptor-deficient (GRKO) leukemia between wild-type (WT) and IFN-γ–deficient (GKO) allogeneic hematopoietic cell transplantation (allo-HCT). We established a primary IFN-γ–unresponsive T-cell leukemia model using virally-transduced GRKO B6 mouse bone marrow cells overexpressing Notch1. We first assessed GVL effects in lethally-irradiated B6 mice receiving CD4-depleted allo-HCT from WT or GKO BALB/c donors. Administration of CD4+ cell-depleted allo-HCT from WT, but not GKO, BALB/c donors mediated significant GVL effects against GRKO leukemia. Similar results were obtained in pre-established allogeneic chimeras receiving delayed donor lymphocyte infusion (DLI). Although both WT and GKO DLI achieved significant anti-tumor responses, the former was markedly stronger than the latter. These data indicate that IFN-γ is capable of promoting GVL effects via mechanisms independent of its interaction with leukemia cells.

Hypomethylating Agents for Relapse after Allogeneic Hematopoietic Cell Transplantation in Myeloid Malignancies: A Case Series and Review of the Literature

2016 ◽  
Vol 135 (4) ◽  
pp. 232-237
Author(s):  
Annie Im ◽  
Anastasios Raptis ◽  
Jing-Zhou Hou ◽  
Cheryl Tompkins ◽  
Melissa Winfield ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
T Cell Activation ◽  
Hematopoietic Cell Transplantation ◽  
Case Series ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Hypomethylating Agents ◽  
Myeloid Malignancies ◽  
Graft Versus Leukemia ◽  
Graft Versus Leukemia Effect

Background/Aims: Relapse is a leading cause of mortality after allogeneic hematopoietic cell transplantation (HCT). Hypomethylating agents (HMAs) have immunomodulatory properties, including augmenting tumor antigen presentation that may enhance the graft-versus-leukemia effect. Moreover, inhibitory effects on T-cell activation and cytokine production may lead to a lower incidence of graft-versus-host disease (GVHD). Our aim was to describe outcomes in patients treated with HMAs for relapse after HCT. Methods: Subjects were retrospectively identified as patients with relapse or loss of donor chimerism after HCT for myeloid malignancies treated with HMAs at the University of Pittsburgh. Results: Thirteen patients were identified, with a median age of 57 years and a median time to relapse of 98 days. Nine of 12 (75%) evaluable patients had a complete remission (CR). Grade I-IV acute GVHD involving the liver occurred in 6 patients. Cases of acute liver GVHD were diagnosed clinically based on the elevation of liver function tests. The median survival was 14.3 months from the time of relapse. Conclusion: HMAs for relapse after HCT can be effective in inducing a CR. This may be due to epigenetic changes and immunomodulatory effects that enhance the graft-versus-leukemia effect. There may be a risk of GVHD, and further exploration into pathophysiology and predisposing factors are warranted.

Influence of Minor Histocompatibility Antigens' Disparities On Graft Versus Host Disease and Overall Survival After Allogeneic Hematopoietic Cell Transplantation From Siblings

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4172-4172
Author(s):  
Monika Dzierzak-Mietla ◽  
Miroslaw Markiewicz ◽  
Urszula Siekiera ◽  
Sylwia Mizia ◽  
Agnieszka Karolczyk ◽  
...  
Keyword(s):  
Overall Survival ◽  
Y Chromosome ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Histocompatibility Antigens ◽  
Minor Histocompatibility Antigens ◽  
Graft Versus Host

Abstract Abstract 4172 Introduction: Minor histocompatibility antigens (MiHA) are acknowledged non-HLA genetic factors which, in case of their incompatibility between the donor and the recipient, may contribute to post-transplant complications and impact the results of transplantation. The aim of this study was to investigate whether immunogenic MiHA disparities in either Graft-versus-Host or Host-versus-Graft direction influence Graft Versus Host Disease (GVHD) and overall survival after allogeneic hematopoietic cell transplantation (allo-HCT) from matched siblings. Methods: Alleles encoding 11 MiHAs: HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1, ACC-2, HwA-9, HwA-10, UGT2B17 and HY were examined in 62 sibling donor/recipient pairs with use of Dynal AllSet mHA typing kit and PCR-SSP method. Only immunogenic MiHA disparities determined in accordance to dbMinor database, with regard to their GVH or HVG direction, were assessed. Median age of donors and recipients was 35(14–60) and 38(14–59) years, respectively. Median time from diagnosis to allo-HCT was 0.62(0.24–12.91) years. Allo-HCTs were performed between 2000–2008 for following indications: AML, ALL, MDS, CML and NHL. The conditioning treatment before allo-HCT was myeloablative (BuCy, TBI/Cy), reduced toxicity (Treo/Flu) or nonmyeloablative. Median follow-up was 3 (0.04–10) years. Results: Immunogenic MiHA mismatches were observed in 42 (68%) donor-recipient pairs: GVH- or HVG- directed in 18 pairs each and bidirectional in 6 pairs. Acute GVHD was observed in 27 patients, in 24 of whom it was severe (grade III or IV) and it was influenced by GVH-directed disparities of MiHA encoded by Y-chromosome (p=0.037), as shown in Fig. 1. Chronic GVHD was diagnosed in 25 patients, in 12 of them extensive, and it's incidence was influenced by the same kind of MiHA disparities (p=0.017), as shown in Fig. 2. Analysis of overall survival showed unfavorable impact of GVH-directed disparities of Y-chromosome encoded MiHAs (p=0.011), as presented in Fig. 3. Conclusions: Mismatches of Y-chromosome encoded MiHAs significantly impact the occurrence of severe acute and extensive chronic GVHD and decrease overall survival. Disclosures: No relevant conflicts of interest to declare.

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