CD4+ and CD8+T-cell reactions against leukemia-associated- or minor-histocompatibility-antigens in AML-patients after allogeneic SCT

Steger, Brigitte; Milosevic, Slavoljub; Doessinger, Georg; Reuther, Susanne; Liepert, Anja; Braeu, Marion; Schick, Julia; Vogt, Valentin; Schuster, Friedhelm R.; Kroell, Tanja; Busch, Dirk H.; Borkhardt, Arndt; Kolb, Hans‐Jochem; Tischer, Johanna; Buhmann, Raymund; Schmetzer, Helga

doi:10.1016/j.imbio.2013.10.008

Cited by 18 publications

(15 citation statements)

References 52 publications

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“…22 Furthermore, leukemia-associated Ags-peptide specific T cells were detected in nearly all AML patients after allogeneic stem cell transplantation, supporting the concept of potential immunologic control of highrisk AML after aHCT. 23 Although higher patient age was not associated with shorter OS in our cohort, interestingly CR at the time of aHCT was not a positive factor for OS, although it was associated with a lower relapse rate in the univariate analysis. Although this could be attributed to intensive post-relapse therapy, another reason maybe the fact that a substantial number of deaths (23 out of 53) did not occur after relapse, and no effect of CR status on NRM was present.…”

Section: Discussioncontrasting

confidence: 47%

Long-term follow-up of therapy-related myelodysplasia and AML patients treated with allogeneic hematopoietic cell transplantation

Finke

Schmoor

Bertz

et al. 2016

Bone Marrow Transplant

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The outcome of patients with therapy-related myelodysplasia (t-MDS) or t-AML is very poor. The only curative treatment option implements allogeneic hematopoietic cell transplantation (aHCT); however, long-term follow-up data beyond 5 years are scarce. Here we report on a cohort of 79 consecutive patients with a median age of 58 years (range (r): 20-76) at transplantation and a median follow-up of 7.5 years (r: 0.07-19.0). Only 19 (24.1%) patients were in CR before aHCT. Non-relapse mortality and relapse rates were 23% (95% confidence interval, 15-35%) and 42% (32-55%) at 5 years, and 32% (22-46%) and 44% (34-57%) at 10 years, respectively. Disease-free survival (DFS) and overall survival (OS) rates were 35% (24-46%) and 38% (27-49%) at 5 years, and 24% (14-36%) and 24% (13-36%) at 10 years, respectively. Although cytogenetic aberrations were associated with shorter DFS and higher relapse risk, persistent disease at the time of transplantation, an unrelated donor and patient age were not associated with shorter OS. In conclusion, long-term survival beyond 10 years of t-MDS/t-AML patients after aHCT is possible, even for refractory patients. Therefore, early donor search and rapid transplantation are warranted, also to decrease the risk of disease-related deterioration of patients' performance status.Bone Marrow Transplantation (2016) 51, 771-777; doi:10.1038/bmt.2015.338; published online 11 January 2016 INTRODUCTION Cytotoxic agents, especially alkylating and topoisomerase II targeting drugs, as well as ionizing radiotherapy in the successful treatment of most cancer types and to some extent also in nonmalignant diseases, bear a significant long-term risk of developing therapy-related malignancies such as myelodysplasia (t-MDS) and t-AML. 1,2 Despite intensive efforts to reduce the risk of developing t-MDS/t-AML by using fewer cycles of dose-intense chemotherapy for a given primary disease and thus to decrease cumulative doses, this late occurring side effect remains a challenging clinical problem. 3 Treatment of t-MDS/t-AML, which often occurs with other comorbidities, is complex and the outcome of patients treated with low-or even high-dose chemotherapy alone remains poor. Beyond other factors, this is especially attributed to older age, therapy resistance and cytogenetic abnormalities including monosomies or complex karyotypes. 4,5 In recent years, it has become evident that the most successful curative treatment concept for t-MDS/t-AML patients resulting in substantial remission rates implements allogeneic hematopoietic cell transplantation (aHCT). Using a myeloablative conditioning regimen in 77% of patients in a cohort of 868 patients with a median age of 40 years, Litzow et al. 6 reported an overall survival (OS) rate of 22% (95% confidence interval (CI), 19-26%) after 5 years, although the non-relapse mortality (NRM) and relapse rate at that time were 48% (95% CI, 44-51%) and 31% (95% CI, 28-34%), respectively. In another study from the European Group for Blood and Marrow Transplantation, Kröger et al. 7...

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Section: Discussioncontrasting

confidence: 47%

Long-term follow-up of therapy-related myelodysplasia and AML patients treated with allogeneic hematopoietic cell transplantation

Finke

Schmoor

Bertz

et al. 2016

Bone Marrow Transplant

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“…Mispairing of T‐cell receptor chains with endogenous T cell receptor (TCR) chains could be avoided by lentiviral transfer and more recently by silencing endogenous TCR with endonucleases prior to transduction . In our own series we found only significant reactivity against PRAME in patients responding to DLI . This finding is in accord with the finding of PRAME‐reactive cytotoxic T precursor cells in healthy persons and not in AML patients…”

Section: Antigen‐specific T Cellssupporting

confidence: 85%

“…Dendritic cells are able to activate naive T cells to specific immune reactions . Both reactive CD8 and CD4 T cells have been found in patients responding to DLI . in vitro generated T‐cell cytotoxicity was predominantly of CD8 positive T cells, but CD4‐positive CTLs were also present .…”

Section: Production Of Dendritic Cells Of Leukemia Originmentioning

confidence: 99%

Hematopoietic stem cell transplantation and cellular therapy

Kolb

2017

HLA

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Allogeneic stem cell transplantation is a form of immunotherapy that has increased the chances of survival for patients with relapsed leukemia and high risk leukemia in remission. The major obstacles are graft-vs-host disease (GVHD) involving vital organs and infections. A most efficacious prophylaxis of GVHD is by depleting of T cells from the graft. However, problems of T-depleted transplants are rejection, slow recovery of the immune system and high incidence of relapse of leukemia and myeloma. The major problem of allogeneic transplantation is the separation of a graft-vs-leukemia (GVL) effect from GVHD. This review will summarize the factors influencing GVHD, ways to exploit rapid advances in our knowledge of histocompatibility, chimerism and tolerance for fostering GVL over GVHD, and in particular the use of cellular therapies including donor lymphocyte infusions for disease control.

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“…Both reactive CD8-positive and CD4-positive T cells have been found in patients responding to DLI (130). In vitro generated T cell cytotoxicity predominantly consisted of CD8-positive T cells, but CD4-positive cytotoxic T cells were also present (119).…”

Section: Improvement Of the Responsementioning

confidence: 99%

Graft-versus-Leukemia Effect Following Hematopoietic Stem Cell Transplantation for Leukemia

et al. 2017

Self Cite

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The success of hematopoietic stem cell transplantation (HSCT) lies with the ability of the engrafting immune system to remove residual leukemia cells via a graft-versus-leukemia effect (GvL), caused either spontaneously post-HSCT or via donor lymphocyte infusion. GvL effects can also be initiated by allogenic mismatched natural killer cells, antigen-specific T cells, and activated dendritic cells of leukemic origin. The history and further application of this GvL effect and the main mechanisms will be discussed and reviewed in this chapter.

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CD4+ and CD8+T-cell reactions against leukemia-associated- or minor-histocompatibility-antigens in AML-patients after allogeneic SCT

Cited by 18 publications

References 52 publications

Long-term follow-up of therapy-related myelodysplasia and AML patients treated with allogeneic hematopoietic cell transplantation

Long-term follow-up of therapy-related myelodysplasia and AML patients treated with allogeneic hematopoietic cell transplantation

Hematopoietic stem cell transplantation and cellular therapy

Graft-versus-Leukemia Effect Following Hematopoietic Stem Cell Transplantation for Leukemia

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