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Hidekazu Itamura, Takero Shindo, Isao Tawara, Yasushi Kubota, Ryusho Kariya, Seiji Okada, Krishna V Komanduri, Shinya Kimura
The efficacy of allogeneic hematopoietic stem cell transplantation for hematologic malignancies is limited by the difficulty in suppressing graft-versus-host disease (GVHD) without compromising graft-versus-tumor (GVT) effects. We previously showed that RAS/MEK/ERK signaling depends on memory differentiation in human T cells, which confers susceptibility to selective inhibition of naive T cells. Actually, antineoplastic MEK inhibitors selectively suppress alloreactive T cells, sparing virus-specific T cells in vitro...
July 7, 2016: JCI Insight
Zhiwei Zhang, Hua Sun, Jianhua Zhang, Chunlei Ge, Suwei Dong, Zhen Li, Ruilei Li, Xiaodan Chen, Mei Li, Yun Chen, Yingying Zou, Zhongyi Qian, Lei Yang, Jinyan Yang, Zhitao Zhu, Zhimin Liu, Xin Song
BACKGROUND Transplantation with allogeneic cells has become a promising modality for cancer therapy, which can induce graft-versus-tumor (GVT) effect. This study was aimed at assessing the safety, efficacy, and tissue type GVT (tGVT) response of transplantation with allogeneic skin tumors to treat chemically-induced skin tumors in mice. MATERIAL AND METHODS FVB/N and ICR mice were exposed topically to chemicals to induce skin tumors. Healthy ICR mice were transplanted with allogeneic skin tumors from FVB/N mice to test the safety...
2016: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Rong Hu, Yalan Liu, Yinhong Song, Min Su, Xiuling Lu, Debra Rood, Laijun Lai
Given that donor T cells from a transplant contribute both the desired graft-versus-tumour (GVT) effect and detrimental graft-versus-host disease (GVHD), strategies to separate GVHD and GVT activity are a major clinical goal. We have previously demonstrated that in vivo administration of a recombinant (r)IL-7/HGFβ hybrid cytokine, consisting of interleukin-7 (IL-7, IL7) and the β-chain of hepatocyte growth factor (HGFβ), significantly inhibits the growth of cancer cells in murine tumour models. The antit-umour effect of rIL-7/HGFβ is related to a marked infiltration T cells in the tumour tissues...
July 22, 2016: British Journal of Haematology
G Chennappa, M K Naik, C R Adkar-Purushothama, Y S Amaresh, M Y Sreenivasa
Azotobacter strains were isolated by serial dilution method and colonies were viscous, smooth, glistening, and brown to black colour on Jenson's N-free agar. Morphological and biochemical tests showed characteristic features of Azotobacter. Further, molecular analyses revealed the presence of different Azotobacter species viz., A. armeniacus, A. chroococcum, A. salinestris, A. tropicalis and A. vinelandii. The isolates were tested for their ability of nitrogen fixation, indole acetic acid (IAA), gibberllic acid production and phosphate solubilization...
May 2016: Indian Journal of Experimental Biology
X-Y Qin, Y Wang, G-X Li, Y-Z Qin, F-R Wang, L-P Xu, H Chen, W Han, J-Z Wang, X-H Zhang, Y-J Chang, K-Y Liu, Z-F Jiang, X-J Huang
BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been established as an effective treatment for patients with hematological malignancies. Disease relapse remains a major cause of transplant failure. T cell homeostasis is critical to determine the potency of the GVT effect. Recent studies have shown the association of the CTLA-4 polymorphisms with the outcome after HLA-identical sibling allogeneic HSCT. METHODS: In this study, we focused on four CTLA-4 polymorphisms, and analyzed the impact of donor genotypes and haplotypes on the conditions of 152 acute leukemia patients (ALL 83) after related HLA-haplotype- mismatched transplantation...
2016: Journal of Translational Medicine
Martin Szyska, Il-Kang Na
The bone marrow is the origin of all hematopoietic lineages and an important homing site for memory cells of the adaptive immune system. It has recently emerged as a graft-versus-host disease (GvHD) target organ after allogeneic stem cell transplantation (alloHSCT), marked by depletion of both hematopoietic progenitors and niche-forming cells. Serious effects on the restoration of hematopoietic function and immunological memory are common, especially in patients after myeloablative conditioning therapy. Cytopenia and durable immunodeficiency caused by the depletion of hematopoietic progenitors and destruction of bone marrow niches negatively influence the outcome of alloHSCT...
2016: Frontiers in Immunology
X Chang, X Zang, C Q Xia
DLI is an effective strategy for patients with recurrent hematological malignancies after allogeneic hematopoietic SCT (allo-HSCT). DLI has been widely applied to boost the graft vs tumor (GVT) or GVL effects. However, given the potentially severe complications associated with conventional DLI and transient GVL effect, new strategies for DLI are emerging. In this review, we have discussed the recent important studies on DLI as a prophylactic or therapeutic modality for relapsed hematological disorders after allo-HSCT...
March 2016: Bone Marrow Transplantation
Kirsten A Thus, Talitha A de Hoop, Roel A de Weger, Marc B Bierings, Jaap Jan Boelens, Eric Spierings
Unrelated cord blood transplantation (UCBT) provides a curative therapy for patients with hematological malignancies. The effect of HLA mismatches in UCBT is currently the subject of debate. HLA-mismatched UCBT may lead to improved leukemia control but also to graft-versus-host disease (GVHD), resulting in nonrelapse mortality (NRM). The aim of this study was to investigate whether indirect recognition of mismatched HLA provides an explanation for the graft-versus-tumor effect and risk of GVHD. The probability of indirect recognition was predicted by the Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) model...
January 2016: Biology of Blood and Marrow Transplantation
Roni Tamari, Stephen S Chung, Esperanza B Papadopoulos, Ann A Jakubowski, Patrick Hilden, Sean M Devlin, Jenna D Goldberg, Miguel-Angel Perales, Doris M Ponce, Craig S Sauter, Molly A Maloy, Dara Y Herman, Virginia Klimek, James W Young, Richard J O'Reilly, Sergio A Giralt, Hugo Castro-Malaspina
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for patients with myelodysplastic syndrome (MDS). Donor T cells are critical for the graft-versus-tumor effect but carry the risk of graft-versus-host disease (GVHD). CD34 selection with immunomagnetic beads has been an effective method of depleting alloreactive donor T cells from the peripheral blood graft and has been shown to result in significant reduction in acute and chronic GVHD. We analyzed the outcomes of 102 adults (median age, 57...
December 2015: Biology of Blood and Marrow Transplantation
Henri Roukoz, Mandar Shah, Lawrence Jesuraj Masilamani, Ajit Thachil, Prem K Jayakumar, David G Benditt, Calambur Narasimhan
BACKGROUND: Granulomatous myocarditis may present with sustained monomorphic ventricular tachycardia (SMVT) in the presence of normal left ventricular ejection fraction (LVEF), and could be mistaken for idiopathic ventricular tachycardia (IVT). The use of cardiac imaging for diagnosis can be limited by availability and high cost. ECG is readily available and inexpensive. Fragmented QRS (fQRS) on ECG has been found to be associated with myocardial scar. We hypothesized that fQRS could be useful in the diagnosis of granulomatous VT (GVT)...
May 2015: Indian Heart Journal
R Qiu, Y Wang, Z Chi
PURPOSE: In premise of uninfluenced to dose distribution of tumor target and organ at risk(OAR) in Nasopharyngeal carcinoma (NPC),the number of segment was changed to increase efficacy and optimize treatment method by designing different plan of intensity modulated radiotherapy(IMRT). METHODS: 10 cases of NPC were confirmed in pathology and treated with step and shoot IMRT. The target volumes were defined: GVT-T (the primary tumor); GVT-N (the metastasis lymph nodes in neck) ; CTV-T and CTV-N (the clinical targets of GVT-T and GTV-N) ; and PTV (incidental lymph nodal region)...
June 2015: Medical Physics
Miriam E Mossoba, David C Halverson, Roger Kurlander, Bazetta Blacklock Schuver, Ashley Carpenter, Brenna Hansen, Seth M Steinberg, Syed Abbas Ali, Nishant Tageja, Frances T Hakim, Juan Gea-Banacloche, Claude Sportes, Nancy M Hardy, Dennis D Hickstein, Steven Z Pavletic, Hanh Khuu, Marianna Sabatini, David Stroncek, Bruce L Levine, Carl H June, Jacopo Mariotti, Olivier Rixe, Antonio Tito Fojo, Michael R Bishop, Ronald E Gress, Daniel H Fowler
PURPOSE: We hypothesized that lymphoid-selective host conditioning and subsequent adoptive transfer of sirolimus-resistant allogeneic T cells (T-Rapa), when combined with high-dose sirolimus drug therapy in vivo, would safely achieve antitumor effects while avoiding GVHD. EXPERIMENTAL DESIGN: Patients (n = 10) with metastatic renal cell carcinoma (RCC) were accrued because this disease is relatively refractory to high-dose conditioning yet may respond to high-dose sirolimus...
October 1, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Byung-Su Kim, Hidekazu Nishikii, Jeanette Baker, Antonio Pierini, Dominik Schneidawind, Yuqiong Pan, Andreas Beilhack, Chung-Gyu Park, Robert S Negrin
The paucity of regulatory T cells (Tregs) limits clinical translation to control aberrant immune reactions including graft-versus-host disease (GVHD). Recent studies showed that the agonistic antibody to DR3 (αDR3) expanded CD4(+)FoxP3(+) Tregs in vivo. We investigated whether treating donor mice with a single dose of αDR3 could alleviate acute GVHD in a MHC-mismatched bone marrow transplantation model. αDR3 induced selective proliferation of functional Tregs. CD4(+) T cells isolated from αDR3-treated mice contained higher numbers of Tregs and were less proliferative to allogeneic stimuli...
July 23, 2015: Blood
Raffaella Greco, Giacomo Oliveira, Maria Teresa Lupo Stanghellini, Luca Vago, Attilio Bondanza, Jacopo Peccatori, Nicoletta Cieri, Sarah Marktel, Sara Mastaglio, Claudio Bordignon, Chiara Bonini, Fabio Ciceri
While opening new frontiers for the cure of malignant and non-malignant diseases, the increasing use of cell therapy poses also several new challenges related to the safety of a living drug. The most effective and consolidated cell therapy approach is allogeneic hematopoietic stem cell transplantation (HSCT), the only cure for several patients with high-risk hematological malignancies. The potential of allogeneic HSCT is strictly dependent on the donor immune system, particularly on alloreactive T lymphocytes, that promote the beneficial graft-versus-tumor effect (GvT), but may also trigger the detrimental graft-versus-host-disease (GvHD)...
2015: Frontiers in Pharmacology
H Joachim Deeg
Although high-dose chemotherapy may cure a small subset of patients with myelodysplastic syndrome (MDS), allogeneic hematopoietic cell transplantation (HCT) is the only currently available modality that is curative in a large proportion of patients. Approximately 30% to 40% of patients with high-risk MDS and 60% to 80% of patients with low-risk MDS survive long-term in remission. Disease classification and risk assessment schemes, such as the World Health Organization (WHO) Prognostic Scoring System (WPSS), the Revised International Prognostic Scoring System (IPSS-R), and patient characteristics as assessed by the HCT Comorbidity Index (HCT-CI) or other scores, provide guidance for patient management...
2015: American Society of Clinical Oncology Educational Book
U Holtick, J M Chemnitz, M Hallek, C Scheid
Allogeneic haematopoietic stem cell transplantation is an effective treatment option for chemotherapy-refractory or relapsed haematological malignancies such as leukaemias and lymphomas. After conditioning with chemotherapy with or without total body irradiation, donor cells are infused to reconstitute haematopoiesis. Donor-derived immune cells induce immune reactions to control or eradicate the underlying disease, thereby going beyond the effect of chemotherapy. This graft-versus-tumour effect (GvT) is often accompanied by detrimental graft-versus-host reactions (graft-versus-host disease, GvHD), which substantially influence the mortality and morbidity after transplantation...
May 2015: Klinische Monatsblätter Für Augenheilkunde
Cristiana Carniti, Silvia Gimondi, Antonio Vendramin, Camilla Recordati, Davide Confalonieri, Anisa Bermema, Paolo Corradini, Jacopo Mariotti
PURPOSE: Immune-mediated graft-versus-tumor (GVT) effects can occur after allogeneic hematopoietic stem cell transplantation (HSCT), but GVT is tightly linked to its main complication, graft-versus-host disease (GVHD). Strategies aimed at modulating GVHD, while maintaining the GVT effect, are needed to improve the cure rate of transplant. Given the emerging role of Janus-activated kinase (JAK) signaling in lymphoproliferative and myeloproliferative diseases and its established function at dictating T-cell differentiation, we postulated that JAKs might be potential therapeutic targets through a pharmacologic approach...
August 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Niklas Beyersdorf, Sandra Werner, Nelli Wolf, Thomas Hünig, Thomas Kerkau
Upon transplantation of T cells from a CD28 superagonist (CD28-SA) treated donor into an irradiated allogeneic host, the CD28-SA-induced activation and expansion of Treg cells inhibits acute graft versus host disease (aGvHD), while not abrogating the desired graft versus tumor effect. Human peripheral blood CD4(+) T cells, however, harbor only very few Treg cells. Therefore, we studied whether polyclonal in vitro prestimulation of conventional, that is Treg -cell-depleted, CD4(+) T cells of C57BL/6 mice with CD28-SA-coated paramagnetic beads is sufficient to protect recipient BALB/c mice from aGvHD...
July 2015: European Journal of Immunology
Muhammad Omer Jamil, Shin Mineishi
Graft-versus-host disease (GVHD) remains as the major obstacle for successful hematopoietic stem cell transplant (HSCT). Roughly half of the patients undergoing HSCT develop GVHD which requires treatment, and above 10 % of the patient may die because of it. However, GVHD presents with anti-tumor activity, called graft-versus-tumor (GVT) effect, and it carries significant anti-tumor activity, thus suppressing GVHD completely may increase the relapse of original disease. Thus, it is important to control GVHD to the appropriate level...
May 2015: International Journal of Hematology
L E Franssen, N W C J van de Donk, M E Emmelot, M W H Roeven, N Schaap, H Dolstra, W Hobo, H M Lokhorst, T Mutis
Allo-SCT followed by DLIs can establish long-term remissions in multiple myeloma (MM) patients. In many patients, however, the immunotherapeutic graft-versus-tumor (GVT) effect is moderate and not sustained, implying that immune suppression is mediated, among other factors, by regulatory T cells (Tregs) or myeloid-derived suppressor cells (MDSCs). Towards a better understanding and, eventually, manipulation of the immune-regulatory mechanisms in transplanted MM patients, we retrospectively sought a correlation between DLI outcome and circulating CD14(+) MDSCs, CD14(-) MDSCs and Tregs in 53 MM patients before their first DLI...
June 2015: Bone Marrow Transplantation
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