Selective graft-versus-leukemia depends on magnitude and diversity of the alloreactive T cell response

T cell responses against malignant cells play a major role in maintaining remission and prolonging overall survival in patients after allogeneic stem cell transplantation and donor lymphocyte infusion (DLI) due to graft-versus-leukemia effect. For better characterization of the T cell responses, we assessed frequency and diversity of leukemia-associated antigen (LAA)-specific cytotoxic T cells using ELISpot and pMHC multimer assays and analyzed the frequency of regulatory T cells (Treg) as well as cytokine profiles before/after DLI. The data were correlated to the clinical course of patients. Significantly more LAA-derived T cell epitopes (p = 0.02) were recognized in clinical responders (R) when compared to nonresponders (NR). In addition, pMHC multimer-based flow cytometry showed a significantly higher frequency of LAA-specific T cells in R versus NR. The frequency of Treg in R decreased significantly (p = 0.008) while keeping stable in NR. No differences in T cell subset analysis before/after DLI were revealed. Clinical responders were correlated to specific immune responses and all clinical responders showed an increase of specific immune responses after DLI. Cytokine assays using enzyme-linked immunosorbent assay showed a significant increase of IL-4 after DLI. Taken together, an increase of specific CTL responses against several LAA after DLI was detected. Moreover, this study suggests that enhanced LAA diversity in T cell responses as well as decreasing numbers of Treg contribute to clinical outcome of patients treated with DLI.

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“…Recently, van Bergen et al . investigated the role of mHag‐specific T cells for GvL‐effect and in GvHD.…”

Section: Discussionmentioning

confidence: 99%

Donor lymphocyte infusion leads to diversity of specific T cell responses and reduces regulatory T cell frequency in clinical responders

Hofmann

Schmitt

Götz

et al. 2018

Intl Journal of Cancer

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“…Its efficacy relies on immunemediated graft-versus-leukaemia (GVL) effects [5][6][7][8][9][10]. Following allogeneic bone marrow (BM) or peripheral blood stem cell (PBSC) transplantation, there is a strong association between occurrence of graft-versus-host disease (GVHD) and a lower risk of AML relapse [11][12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

“…Allogeneic umbilical cord blood transplantation (UCBT) is a treatment option for many patients with acute myeloid leukaemia (AML) who lack an HLAmatched donor [1][2][3][4]. Its efficacy relies on immunemediated graft-versus-leukaemia (GVL) effects [5][6][7][8][9][10]. Following allogeneic bone marrow (BM) or peripheral blood stem cell (PBSC) transplantation, there is a strong association between occurrence of graft-versus-host disease (GVHD) and a lower risk of AML relapse [11][12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Occurrence of graft‐versus‐host disease increases mortality after umbilical cord blood transplantation for acute myeloid leukaemia: a report from Eurocord and the ALWP of the EBMT

et al. 2017

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Background The efficacy of umbilical cord blood transplantation (UCBT) as treatment for acute myeloid leukaemia (AML) relies on immune‐mediated graft‐versus‐leukaemia effects. Previous studies have suggested a strong association between graft‐versus‐host disease (GVHD) occurrence and graft‐versus‐leukaemia effects after allogeneic hematopoietic cell transplantation. Methods Here, we evaluated the kinetics of relapse rate in correlation with GVHD occurrence after UCBT. The kinetics of relapse rate over time in correlation to GVHD occurrence were assessed by calculating the relapse rate per patient‐year within sequential 90‐day intervals. The impact of GVHD on relapse and mortality was further studied in multivariate Cox models handling GVHD as a time‐dependent covariate. Results The study included data from 1068 patients given single (n = 567) or double (n = 501) UCBT. The proportion of patients with grade II, III and IV acute GVHD was 20%, 7% and 4%, respectively. At 2 years, the cumulative incidence of chronic GVHD was 42%, the cumulative incidence of relapse was 32%, and overall survival was 32% as well. Relapse rates declined gradually over time during the first 30 months after transplantation. There was a possible suggestion that grade II–IV acute (HR = 0.8, P = 0.1) and chronic (HR = 0.65, P = 0.1) GVHD decreased relapse risk. However, grade II–IV acute GVHD significantly increased early (the first 18 months after UCBT) mortality (HR = 1.3, P = 0.02), whilst chronic GVHD increased each early (HR = 2.7, P < 0.001) and late (HR = 4.9, P < 0.001) mortality after UCBT. Conclusions The occurrence of grade II–IV acute or chronic GVHD each increases overall mortality after UCBT for AML mitigating the possible graft‐versus‐leukemia effect of GVHD.

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“…puc2CL6IP HLA-B*27:05/09 constructs (kind gift of Dr. S. Springer(11)) were co-transfected using PEI with packaging plasmids pVSVg and NLBH into HEK293T cells for virus production. Viral supernatants of other HLA alleles contained a ΔNGFR marker gene (kind gift of Dr. M Griffioen) (12). Viral supernatant was filtered and used for transduction by spinoculation in the presence of 8 μg/mL protamine sulfate.…”

Section: Methodsmentioning

confidence: 99%

PAKC: A novel Panel of HLA class I Antigen presentation machinery Knockout Cells from the same genetic origin

Waard

Verkerk

Jongsma

et al. 2020

Preprint

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With the emergence of immunotherapies, the understanding of functional HLA class I antigen presentation to T cells is more relevant than ever. Current knowledge on antigen presentation is based on decades of research in a wide variety of cell types with varying antigen presentation machinery (APM) expression patterns, proteomes and HLA haplotypes. This diversity complicates the establishment of individual APM contributions to antigen generation, selection and presentation. Therefore, we generated a novel Panel of APM Knockout Cell lines (PAKC) from the same genetic origin. After CRISPR/Cas9 genome-editing of ten individual APM components in a human cell line, we derived clonal cell lines and confirmed their knockout status and phenotype. We then show how PAKC will accelerate research on the functional interplay between APM components and their role in antigen generation and presentation. This will lead to improved understanding of peptide-specific T cell responses in infection, cancer and autoimmunity.Key pointsWe generated a panel of cell lines to study HLA class I antigen presentationWe show how this will spark research in infection, tumor biology and autoimmunity

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Selective graft-versus-leukemia depends on magnitude and diversity of the alloreactive T cell response

Cited by 91 publications

References 51 publications

Donor lymphocyte infusion leads to diversity of specific T cell responses and reduces regulatory T cell frequency in clinical responders

Donor lymphocyte infusion leads to diversity of specific T cell responses and reduces regulatory T cell frequency in clinical responders

Occurrence of graft‐versus‐host disease increases mortality after umbilical cord blood transplantation for acute myeloid leukaemia: a report from Eurocord and the ALWP of the EBMT

PAKC: A novel Panel of HLA class I Antigen presentation machinery Knockout Cells from the same genetic origin

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