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Graft-versus-leukemia

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https://www.readbyqxmd.com/read/28721499/treg-protected-donor-lymphocyte-infusions-a-new-tool-to-address-the-graft-versus-leukemia-effect-in-the-absence-of-graft-versus-host-disease-in-patients-relapsed-after-hsct
#1
Mauro Di Ianni, Paola Olioso, Raffaella Giancola, Stella Santarone, Annalisa Natale, Gabriele Papalinetti, Ida Villanova, Stefano Baldoni, Ambra Di Tommaso, Tiziana Bonfini, Patrizia Accorsi, Paolo Di Bartolomeo
In high-risk acute leukemia patients undergoing haploidentical hematopoietic stem cell transplantation (HSCT), adoptive immunotherapy with T regulatory cells (Tregs) and T conventional cells (Tcons) prevented acute and chronic graft-versus-host disease (GvHD), favored post-transplant immunological reconstitution and was associated with a powerful graft-versus-leukemia (GvL) effect. With a particularly innovative approach, we developed a treatment with a Treg-protected donor lymphocyte infusion (DLI) for patients with early relapse after HSCT and we report here the results obtained in the first patient with APL (M3v) relapsed after a second matched allogeneic HSCT (15% blasts and 75% of donor cells in bone marrow)...
July 18, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28667011/hla-dp-in-unrelated-hematopoietic-cell-transplantation-revisited-challenges-and-opportunities
#2
Katharina Fleischhauer, Bronwen E Shaw
When considering HLA-matched hematopoietic cell transplantation (HCT), sibling and unrelated donors (UD) are biologically different because UD-HCT is typically performed across HLA-DP disparities absent in sibling-HCT. Mismatched HLA-DP is the target of direct alloreactive T-cell responses with important implications for graft-versus-host-disease and graft-versus-leukemia. This concise review details the special features of HLA-DP as model antigens for clinically permissive mismatches mediating limited T-cell alloreactivity with minimal toxicity, and describes future avenues for their exploitation in cellular immunotherapy of malignant blood disorders...
June 30, 2017: Blood
https://www.readbyqxmd.com/read/28652579/hla-dpb1-mismatch-induces-a-graft-versus-leukemia-effect-without-severe-acute-gvhd-after-single-unit-umbilical-cord-blood-transplantation
#3
T Yabe, F Azuma, K Kashiwase, K Matsumoto, T Orihara, H Yabe, S Kato, K Kato, S Kai, T Mori, S Morishima, M Satake, M Takanashi, K Nakajima, Y Morishima
Although it is known that human leukocyte antigen (HLA)-DPB1 disparity has a strong impact on outcomes in unrelated hematopoietic transplantation with induction of acute graft-versus-host disease (GVHD) and a graft-versus-leukemia (GVL) effect, its role in unrelated umbilical cord blood transplantation (UR-CBT) has yet to be fully clarified. Our current study is being conducted to elucidate the impact of HLA-DPB1 mismatch, along with the effect of other HLA loci mismatches at the allele level. HLA six loci alleles were retrospectively typed in 1157 Japanese donors and patients with leukemia or myelodysplastic syndrome who underwent transplantation with a single unit of cord blood...
June 27, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28646023/amlexanox-downregulates-s100a6-to-sensitize-kmt2a-aff1-positive-acute-lymphoblastic-leukemia-to-tnf-%C3%AE-treatment
#4
Hayato Tamai, Hiroki Yamaguchi, Koichi Miyake, Miyuki Takatori, Tomoaki Kitano, Satoshi Yamanaka, Syunsuke Yui, Keiko Fukunaga, Kazutaka Nakayama, Koiti Inokuchi
Acute lymphoblastic leukemias (ALL) positive for KMT2A/AFF1 (MLL/AF4) translocation, which constitute 60% of all infant ALL cases, have a poor prognosis even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This poor prognosis is due to one of two factors, either resistance to TNF-α which mediates a graft-versus-leukemia (GVL) response after allo-HSCT, or immune resistance due to upregulated expression of the immune escape factor S100A6. Here we report an immune stimulatory effect against KMT2A/AFF1-positive ALL cells by treatment with the anti-allergy drug amlexanox, which we found to inhibit S100A6 expression in the presence of TNF-α...
June 23, 2017: Cancer Research
https://www.readbyqxmd.com/read/28641099/reduced-intensity-versus-myeloablative-allogeneic-transplantation
#5
REVIEW
Daniel J Weisdorf
Allotransplantation cures patients by cytoreduction and the graft-versus-tumor (leukemia; graft-versus-leukemia [GVL]) alloresponse; both eliminate residual disease. The spectrum of conditioning intensity influences toxicities and non-relapse mortality. The spectrum of tumor sensitivity to the GVL response influences relapse. Balancing tolerable toxicities (influenced by patients' performance status and comorbidities) is also influenced by the graft. Intense immunosuppression (for engraftment and graft-versus-host disease prevention) may constrain the immunologic potency of the graft and limit the antineoplastic capacity of the transplant, thus requiring more intense or more effective conditioning regimens to limit the risks of relapse and permit satisfactory disease-free survival...
June 14, 2017: Hematology/oncology and Stem Cell Therapy
https://www.readbyqxmd.com/read/28638744/azacytidine-prevents-experimental-xenogeneic-graft-versus-host-disease-without-abrogating-graft-versus-leukemia-effects
#6
Grégory Ehx, Gilles Fransolet, Laurence de Leval, Stéphanie D'Hondt, Sophie Lucas, Muriel Hannon, Loïc Delens, Sophie Dubois, Pierre Drion, Yves Beguin, Stéphanie Humblet-Baron, Frédéric Baron
The demethylating agent 5-azacytidine (AZA) has proven its efficacy in the treatment of myelodysplastic syndrome and acute myeloid leukemia. In addition, AZA can demethylate FOXP3 intron 1 (FOXP3i1) leading to the generation of regulatory T cells (Treg). Here, we investigated the impact of AZA on xenogeneic graft-vs.-host disease (xGVHD) and graft-vs.-leukemia effects in a humanized murine model of transplantation (human PBMCs-infused NSG mice), and described the impact of the drug on human T cells in vivo...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28638379/graft-versus-leukemia-effect-following-hematopoietic-stem-cell-transplantation-for-leukemia
#7
REVIEW
Anne M Dickinson, Jean Norden, Shuang Li, Ilona Hromadnikova, Christoph Schmid, Helga Schmetzer, Hans Jochem-Kolb
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...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28636890/memory-t-cells-a-helpful-guard-for-allogeneic-hematopoietic-stem-cell-transplantation-without-causing-graft-versus-host-disease
#8
REVIEW
Wei Huang, Nelson J Chao
Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (AHSCT) and the major cause of nonrelapse morbidity and mortality of AHSCT. In AHSCT, donor T cells facilitate hematopoietic stem cell (HSC) engraftment, contribute to anti-infection immunity, and mediate graft-versus-leukemia (GVL) responses. However, activated alloreactive T cells also attack recipient cells in vital organs, leading to GVHD. Different T-cell subsets, including naïve T (TN) cells, memory T (TM) cells, and regulatory T (Treg) cells mediate different forms of GVHD and GVL; TN cells mediate severe GVHD, whereas TM cells do not cause GVHD, but preserve T-cell function including GVL...
June 13, 2017: Hematology/oncology and Stem Cell Therapy
https://www.readbyqxmd.com/read/28607921/graft-predominance-after-double-umbilical-cord-blood-transplantation-a-review
#9
REVIEW
Jan J Cornelissen, Burak Kalin, Cor H J Lamers
Several parameters are involved in graft predominance after double umbilical cord blood transplantation (dUCBT), of which T-cell alloreactivity between the grafts is now considered to be the major denominator. We recently showed that alloreactive CD4+ T-cells originating from the predominant CBU recognize HLA-class II allele mismatches and can readily be detected in the majority of patients. In addition, it was shown that HLA-class II allele-specific CD4+ T-cells were able to recognize primary leukemic cells when the mismatched HLA-class II allele was shared between the rejected CBU and the patient...
2017: Stem Cell Investigation
https://www.readbyqxmd.com/read/28604385/differential-requirements-for-myeloid-leukemia-ifn-%C3%AE-conditioning-determine-graft-versus-leukemia-resistance-and-sensitivity
#10
Catherine Matte-Martone, Jinling Liu, Meng Zhou, Maria Chikina, Douglas R Green, John T Harty, Warren D Shlomchik
The graft-versus-leukemia (GVL) effect in allogeneic hematopoietic stem cell transplantation (alloSCT) is potent against chronic phase chronic myelogenous leukemia (CP-CML), but blast crisis CML (BC-CML) and acute myeloid leukemias (AML) are GVL resistant. To understand GVL resistance, we studied GVL against mouse models of CP-CML, BC-CML, and AML generated by the transduction of mouse BM with fusion cDNAs derived from human leukemias. Prior work has shown that CD4+ T cell-mediated GVL against CP-CML and BC-CML required intact leukemia MHCII; however, stem cells from both leukemias were MHCII negative...
June 30, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28587506/extracorporeal-photopheresis-for-gvhd-prophylaxis-after-reduced-intensity-conditioning-allogeneic-hematopoietic-stem-cell-transplantation-a-prospective-multicenter-phase-2-study
#11
Mauricette Michallet, Mohamad Sobh, Frederic Garban, Claude Eric Bulabois, Ibrahim Yakoub-Agha, Valerie Coiteux, Remy Dulery, Pierre-Simon Rohrlich, Faezeh Legrand, Laurence Clement, Aline Praire, Marie Detrait, Fiorenza Barraco, Franck Emmanuel Nicolini, Olivier Hequet
We performed a prospective multicenter phase 2 study to evaluate the safety and efficacy of prophylactic Extracorporeal Photopheresis (ECP) in adult patients with hematological malignancies early after RIC allo-HSCT on day 21 twice per week during the first two weeks and then once per week for the next four weeks for a total of eight ECP courses. A total of 20 patients were included; 10 were males, median age was 60 years. All patients engrafted, 17 (85%) received the total eight ECP courses. There were no adverse effects related to ECP...
June 7, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28536356/hla-c-kir-ligands-determine-the-impact-of-anti-thymocyte-globulin-atg-on-graft-versus-host-and-graft-versus-leukemia-effects-following-hematopoietic-stem-cell-transplantation
#12
Johannes Clausen, Alexandra Böhm, Irene Straßl, Olga Stiefel, Veronika Buxhofer-Ausch, Sigrid Machherndl-Spandl, Josef König, Stefan Schmidt, Hansjörg Steitzer, Martin Danzer, Hedwig Kasparu, Ansgar Weltermann, David Nachbaur
Rabbit anti-thymocyte globulins (ATGs) are widely used for the prevention of acute and chronic graft versus host disease (aGVHD, cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT). However, most prospective and retrospective studies did not reveal an overall survival (OS) benefit associated with ATG. Homozygosity for human leukocyte antigen (HLA)-C group 1 killer-cell immunoglobulin-like receptor ligands (KIR-L), i.e. C1/1 KIR-L status, was recently shown to be a risk factor for severe aGVHD...
March 28, 2017: Biomedicines
https://www.readbyqxmd.com/read/28520526/kir3dl1-hl-a-b-subtypes-govern-acute-myelogenous-leukemia-relapse-after-hematopoietic-cell-transplantation
#13
Jeanette E Boudreau, Fabio Giglio, Ted A Gooley, Philip A Stevenson, Jean-Benoît Le Luduec, Brian C Shaffer, Raja Rajalingam, Lihua Hou, Carolyn Katovich Hurley, Harriet Noreen, Elaine F Reed, Neng Yu, Cynthia Vierra-Green, Michael Haagenson, Mari Malkki, Effie W Petersdorf, Stephen Spellman, Katharine C Hsu
Purpose Disease relapse remains a major challenge to successful outcomes in patients who undergo allogeneic hematopoietic cell transplantation (HCT). Donor natural killer (NK) cell alloreactivity in HCT can control leukemic relapse, but capturing alloreactivity in HLA-matched HCT has been elusive. HLA expression on leukemia cells-upregulated in the post-HCT environment-signals for NK cell inhibition via inhibitory killer immunoglobulin-like (KIR) receptors and interrupts their antitumor activity. We hypothesized that varied strengths of inhibition among subtypes of the ubiquitous KIR3DL1 and its cognate ligand, HLA-B, would titrate NK reactivity against acute myelogenous leukemia (AML)...
July 10, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28423578/endothelial-microparticles-delivering-microrna-155-into-t-lymphocytes-are-involved-in-the-initiation-of-acute-graft-versus-host-disease-following-allogeneic-hematopoietic-stem-cell-transplantation
#14
Ran Zhang, Xiaoxiao Wang, Mei Hong, Ting Luo, Miaomiao Zhao, Haorui Shen, Jun Fang, Xiaojie Li, Sibin Zang, Ping Chen, Dimin Nie, Peng Zheng, Qiuling Wu, Linghui Xia
Endothelial microparticles (EMPs) upregulation has been observed in acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the role of EMPs remains unclear. We found that EMPs derived from TNF-α-stimulated human umbilical vein endothelial cells (EA.hy926) concentrated more microRNA-155 (miR-155) compared with maternal cells. The miR-155 levels in MPs from peripheral blood of aGVHD patients and mice were remarkably elevated and significantly higher than the levels in plasma...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414300/pd-l1-serves-as-a-double-agent-in-separating-gvl-from-gvhd
#15
Todd V Brennan, Yiping Yang
Allogeneic hematopoietic cell transplantation (HCT) represents a potentially curative treatment for a variety of hematologic malignancies due to the well-recognized graft-versus-leukemia/lymphoma (GVL) effect that is mediated by donor-derived alloreactive T cells. However, graft-versus-host disease (GVHD) is mediated by the same T cells and remains a significant clinical problem associated with substantial morbidity and mortality. In this issue of the JCI, Ni and colleagues used several murine models of GVHD to evaluate the effect of CD4+ T cell depletion on GVL versus GVHD and revealed that depletion of CD4+ T cells leads to the upregulation of PD-L1 by recipient tissues and donor CD8+ T cells...
May 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28414296/pd-l1-interacts-with-cd80-to-regulate-graft-versus-leukemia-activity-of-donor-cd8-t-cells
#16
Xiong Ni, Qingxiao Song, Kaniel Cassady, Ruishu Deng, Hua Jin, Mingfeng Zhang, Haidong Dong, Stephen Forman, Paul J Martin, Yuan-Zhong Chen, Jianmin Wang, Defu Zeng
Programmed death ligand-1 (PD-L1) interacts with programmed death-1 (PD-1) and the immunostimulatory molecule CD80 and functions as a checkpoint to regulate immune responses. The interaction of PD-L1 with CD80 alone has been shown to exacerbate the severity of graft-versus-host disease (GVHD), whereas costimulation of CD80 and PD-1 ameliorates GVHD. Here we have demonstrated that temporary depletion of donor CD4+ T cells early after hematopoietic cell transplantation effectively prevents GVHD while preserving strong graft-versus-leukemia (GVL) effects in allogeneic and xenogeneic murine GVHD models...
May 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28405514/regulatory-b-cells-promote-graft-versus-host-disease-prevention-and-maintain-graft-versus-leukemia-activity-following-allogeneic-bone-marrow-transplantation
#17
Yue Hu, Gan-Lin He, Xiang-Yu Zhao, Xiao-Su Zhao, Yu Wang, Lan-Ping Xu, Xiao-Hui Zhang, Xue-Zhong Yu, Kai-Yan Liu, Ying-Jun Chang, Xiao-Jun Huang
Regulatory B cells (Bregs) are involved in the pathogenesis of graft-versus-host disease (GVHD). However, whether Bregs can alleviate acute GVHD without compromising graft-versus-leukemia (GVL) effects remains unclear. Here, we evaluated the role of Bregs in acute GVHD and GVL activity in both a mouse model and a clinical cohort study. In the acute GVHD mouse model, co-transplantation of Bregs prevents onset through inhibiting Th1 and Th17 differentiation and expanding regulatory T cells. In the GVL mouse model, Bregs contributed to the suppression of acute GVHD but had no adverse effect on GVL activity...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28396161/isolated-extramedullary-relapse-of-acute-leukemia-after-allogeneic-stem-cell-transplantation-different-kinetics-and-better-prognosis-than-systemic-relapse
#18
Noga Shem-Tov, Francesco Saraceni, Ivetta Danylesko, Roni Shouval, Ronit Yerushalmi, Arnon Nagler, Avichai Shimoni
Allogeneic stem cell transplantation (SCT) is curative treatment in patients with acute leukemia and myelodysplastic syndrome. However, recurrent disease is the major cause of treatment failure. Isolated extramedullary relapse (iEMR) after SCT is relatively rare and not well characterized. We performed a retrospective analysis of 566 consecutive patients with acute myeloid leukemia (n = 446) and acute lymphoblastic leukemia (ALL; n = 120) after SCT to study the incidence, risk factors, treatment options, and outcome of iEMR...
July 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28375154/type-2-innate-lymphoid-cells-treat-and-prevent-acute-gastrointestinal-graft-versus-host-disease
#19
Danny W Bruce, Heather E Stefanski, Benjamin G Vincent, Trisha A Dant, Shannon Reisdorf, Hemamalini Bommiasamy, David A Serody, Justin E Wilson, Karen P McKinnon, Warren D Shlomchik, Paul M Armistead, Jenny P Y Ting, John T Woosley, Bruce R Blazar, Dietmar M W Zaiss, Andrew N J McKenzie, James M Coghill, Jonathan S Serody
Acute graft-versus-host disease (aGVHD) is the most common complication for patients undergoing allogeneic stem cell transplantation. Despite extremely aggressive therapy targeting donor T cells, patients with grade III or greater aGVHD of the lower GI tract, who do not respond to therapy with corticosteroids, have a dismal prognosis. Thus, efforts to improve understanding of the function of local immune and non-immune cells in regulating the inflammatory process in the GI tract during aGVHD are needed. Here, we demonstrate, using murine models of allogeneic BMT, that type 2 innate lymphoid cells (ILC2s) in the lower GI tract are sensitive to conditioning therapy and show very limited ability to repopulate from donor bone marrow...
May 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28330901/azacitidine-mitigates-graft-versus-host-disease-via-differential-effects-on-the-proliferation-of-t-effectors-and-natural-regulatory-t-cells-in-vivo
#20
Matthew L Cooper, Jaebok Choi, Darja Karpova, Kiran Vij, Julie Ritchey, Mark A Schroeder, John F DiPersio
Azacitidine (AzaC) mitigates graft-versus-host disease (GvHD) in both murine preclinical transplant models and in human clinical trials while maintaining a robust graft-versus-leukemia effect. Previous studies have failed to investigate the role of natural regulatory T cells (nTregs) on the mitigation of GvHD by AzaC, instead focusing on the generation of suppressive Tregs (CD4(+)CD25(+)FOXP3(+)) through the in vivo conversion of alloreactive donor T effectors (Teffs; CD4(+)CD25(-)FOXP3(-)) and the direct antiproliferative effects of AzaC on allogeneic T cells...
May 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
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