Publications by authors named "Shin Mineishi"

88 Publications

Alloantigen-activated (AAA) CD4 T cells reinvigorate host endogenous T cell immunity to eliminate pre-established tumors in mice.

J Exp Clin Cancer Res 2021 Oct 8;40(1):314. Epub 2021 Oct 8.

Department of Pediatric Oncology, Fukushima Medical University Hospital, 1 Hikarigaoka, 960-1295, Fukushima City, Japan.

Background: Cancer vaccines that induce endogenous antitumor immunity represent an ideal strategy to overcome intractable cancers. However, doing this against a pre-established cancer using autologous immune cells has proven to be challenging. "Allogeneic effects" refers to the induction of an endogenous immune response upon adoptive transfer of allogeneic lymphocytes without utilizing hematopoietic stem cell transplantation. While allogeneic lymphocytes have a potent ability to activate host immunity as a cell adjuvant, novel strategies that can activate endogenous antitumor activity in cancer patients remain an unmet need. In this study, we established a new method to destroy pre-developed tumors and confer potent antitumor immunity in mice using alloantigen-activated CD4 (named AAA-CD4) T cells.

Methods: AAA-CD4 T cells were generated from CD4 T cells isolated from BALB/c mice in cultures with dendritic cells (DCs) induced from C57BL/6 (B6) mice. In this culture, allogeneic CD4 T cells that recognize and react to B6 mouse-derived alloantigens are preferentially activated. These AAA-CD4 T cells were directly injected into the pre-established melanoma in B6 mice to assess their ability to elicit antitumor immunity in vivo.

Results: Upon intratumoral injection, these AAA-CD4 T cells underwent a dramatic expansion in the tumor and secreted high levels of IFN-γ and IL-2. This was accompanied by markedly increased infiltration of host-derived CD8 T cells, CD4 T cells, natural killer (NK) cells, DCs, and type-1 like macrophages. Selective depletion of host CD8 T cells, rather than NK cells, abrogated this therapeutic effect. Thus, intratumoral administration of AAA-CD4 T cells results in a robust endogenous CD8 T cell response that destroys pre-established melanoma. This locally induced antitumor immunity elicited systemic protection to eliminate tumors at distal sites, persisted over 6 months in vivo, and protected the animals from tumor re-challenge. Notably, the injected AAA-CD4 T cells disappeared within 7 days and caused no adverse reactions.

Conclusions: Our findings indicate that AAA-CD4 T cells reinvigorate endogenous cytotoxic T cells to eradicate pre-established melanoma and induce long-term protective antitumor immunity. This approach can be immediately applied to patients with advanced melanoma and may have broad implications in the treatment of other types of solid tumors.
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http://dx.doi.org/10.1186/s13046-021-02102-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8499505PMC
October 2021

[The coronavirus disease 2019 (COVID-19) and hematologic oncology or BMT practice at our center in US].

Rinsho Ketsueki 2021 ;62(8):998-1003

Penn State Hershey Medical Center, Blood and Marrow Transplant Program.

The coronavirus disease 2019 (COVID-19) pandemic has exerted a considerable impact in our region; thus, we have been performing only emergency transplants in March 2020. At present, all inpatients and surgical patients are being tested and screened for COVID-19. If they are found to be positive, they are transferred to the COVID-19 ward, where a specialized team manages them. Team-based care allows the hematology/oncology teams to perform their regular duties. In particular, for post-transplant patients, treatment decisions are made through discussion with infectious disease specialists, and in principle, the patients are treated using the same protocol as that used for the general COVID-19 infected patients. Currently, vaccination is being promoted at a rapid pace based on the Centers for Disease Control and Prevention Guidelines (CDC) guidelines. At our institution, when a situation of suspected nosocomial COVID-19 infection occurred, all healthcare workers were tested. Thereafter, all hospitalized patients were tested every week for COVID-19, and we were able to overcome the situation. Although definitive measures for COVID-19 are yet to be established, signs of an end to the infection are beginning to appear with a wider availability of vaccines.
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http://dx.doi.org/10.11406/rinketsu.62.998DOI Listing
September 2021

Improved outcome in AML relapse after allogeneic transplant with high-intensity chemotherapy followed by 2nd allogeneic stem cell transplant or donor lymphocyte infusion.

Ann Hematol 2021 Oct 29;100(10):2585-2592. Epub 2021 Jul 29.

Department of Medicine, Penn State Cancer Institute, 500 University Dr., Hershey, PA, 17033, USA.

Acute myeloid leukemia (AML) relapse after allogeneic stem cell transplant (alloSCT) remains a major therapeutic challenge. While patients with longer remission after initial alloSCT are recommended to receive cell therapy (CT) such as 2alloSCT or donor lymphocyte infusion (DLI), survival for patients who relapse within 6 months of alloSCT has been dismal. We evaluated the outcomes of AML relapse after alloSCT to assess the impact of different treatments on long-term survival. One hundred and seventy-two patients with AML underwent alloSCT at the Penn State Cancer Institute from January 2014 to August 2019. Sixty-nine patients relapsed (median age, 60 years; range, 10-75). Of these, 4 patients underwent 2alloSCT, and 26 received DLI. One-year overall survival (OS) in all cases was 20.3% (95% CI: 11.8-30.4%). Patients with ECOG performance status (PS) 0-2 at relapse showed a better 1-year OS than those with PS 3-4. Median OS for patients who received chemotherapy only or chemotherapy with CT was 74 or 173.5 days, respectively (p < 0.001). Relapsed patients receiving conventional re-induction chemotherapy were categorized as the high-intensity chemotherapy (H) group, while those receiving treatments such as hypomethylating agents or targeted agents were categorized as the low-intensity chemotherapy (L) group. The H group showed a better 1-year OS compared with the L group. Patients who received H + CT showed a better 1-year OS of 52.9% than the other 3 groups (p < 0.001). Even for patients with post-alloSCT remission duration of less than 6 months, the statistical significance was preserved. Factors including age, donor source at 1alloSCT, time to relapse, blast counts, PS at relapse, and treatment type after post-alloSCT relapse were used for a multivariate analysis, and matched or mismatched related donor and H + CT after alloSCT were identified as independent factors associated with OS. These findings support the use of H + CT as the treatment option of choice for AML patients who relapse after alloSCT when feasible.
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http://dx.doi.org/10.1007/s00277-021-04616-7DOI Listing
October 2021

A novel clinically relevant graft-versus-leukemia model in humanized mice.

J Leukoc Biol 2021 May 31. Epub 2021 May 31.

Penn State Cancer Institute, Penn State University College of Medicine, Hershey, Pennsylvania, USA.

The prognosis for acute myeloid leukemia (AML) relapse post allogeneic hematopoietic stem cell transplantation (alloSCT) is dismal. Novel effective treatment is urgently needed. Clinical benefit of alloSCT greatly relies on the graft-versus-leukemia (GVL) effect. The mechanisms that mediate immune escape of leukemia (thus causing GVL failure) remain poorly understood. Studies of human GVL have been hindered by the lack of optimal clinically relevant models. Here, using our large, longitudinal clinical tissue bank that include AML cells and G-CSF mobilized donor hematopoietic stem cells (HSCs), we successfully established a novel GVL model in humanized mice. Donor HSCs were injected into immune-deficient NOD-Cg-Prkdc IL2rg /SzJ (NSG) mice to build humanized mice. Immune reconstitution in these mice recapitulated some clinical scenario in the patient who received the corresponding HSCs. Allogeneic but HLA partially matched patient-derived AML cells were successfully engrafted in these humanized mice. Importantly, we observed a significantly reduced (yet incomplete elimination of) leukemia growth in humanized mice compared with that in control NSG mice, demonstrating a functional (but defective) GVL effect. Thus, for the first time, we established a novel humanized mouse model that can be used for studying human GVL responses against human AML cells in vivo. This novel clinically relevant model provides a valuable platform for investigating the mechanisms of human GVL and development of effective leukemia treatments.
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http://dx.doi.org/10.1002/JLB.5AB0820-542RRDOI Listing
May 2021

[Transplant conditioning revisited].

Authors:
Shin Mineishi

Rinsho Ketsueki 2020 ;61(9):1411-1416

Blood and Marrow Transplant Program, Penn State Hershey Medical Center.

Treatment of acute leukemia has evolved rapidly over the past 10 years. Moreover, the role of hematopoietic stem cell transplantation (HSCT) in such treatments has been changing. With the refinement of molecular-targeted therapy and other new modalities, HSCT is no longer the only curative option for leukemia. Nowadays, HSCT is being incorporated into the comprehensive scheme of leukemia treatment and is being compared to other treatment options. This was made possible through the effort to decrease nonrelapse mortality associated with HSCT to levels comparable with those of other modalities. In this review, we will particularly focus on transplantation in patients with aggressive leukemia and graft failure and discuss the role of conditioning regimens for HSCT in the new era of targeted therapy.
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http://dx.doi.org/10.11406/rinketsu.61.1411DOI Listing
January 2021

Graft-versus-host disease depletes plasmacytoid dendritic cell progenitors to impair tolerance induction.

J Clin Invest 2021 01;131(1)

Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, Pennsylvania, USA.

Graft-versus-host disease (GVHD) causes failed reconstitution of donor plasmacytoid dendritic cells (pDCs) that are critical for immune protection and tolerance. We used both murine and human systems to uncover the mechanisms whereby GVHD induces donor pDC defects. GVHD depleted Flt3-expressing donor multipotent progenitors (MPPs) that sustained pDCs, leading to impaired generation of pDCs. MPP loss was associated with decreased amounts of MPP-producing hematopoietic stem cells (HSCs) and oxidative stress-induced death of proliferating MPPs. Additionally, alloreactive T cells produced GM-CSF to inhibit MPP expression of Tcf4, the transcription factor essential for pDC development, subverting MPP production of pDCs. GM-CSF did not affect the maturation of pDC precursors. Notably, enhanced recovery of donor pDCs upon adoptive transfer early after allogeneic HSC transplantation repressed GVHD and restored the de novo generation of donor pDCs in recipient mice. pDCs suppressed the proliferation and expansion of activated autologous T cells via a type I IFN signaling-dependent mechanism. They also produced PD-L1 and LILRB4 to inhibit T cell production of IFN-γ. We thus demonstrate that GVHD impairs the reconstitution of tolerogenic donor pDCs by depleting DC progenitors rather than by preventing pDC maturation. MPPs are an important target to effectively bolster pDC reconstitution for controlling GVHD.
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http://dx.doi.org/10.1172/JCI136774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773406PMC
January 2021

Unexpected Short-Tandem-Repeat Patterns in Posttransplant Chimerism Testing: Investigation of 3 Cases with Help from Forensic Science.

Lab Med 2020 Nov;51(6):635-641

Department of Pathology, Penn State Milton S. Hershey Medical Center, Hershey, PA.

Chimerism testing by short tandem repeats (STRs) is used to monitor engraftment after allogeneic hematopoietic stem cell transplantation (HSCT). Generally, STR alleles are stable and transferred from parent to child or from donor to recipient. However, 3 cases did not follow this norm. Additional work-up with help from forensic literature solved these mysteries. In case 1, the patient received HSCT from his son. The son shared STR alleles in 22/23 loci except Penta E, which was explained by repeat expansion in the son. In case 2, the patient had been in remission for 14 years after HSCT for lymphoma and developed repeat expansion in CSF1PO in granulocytes. In case 3, a pre-HSCT patient demonstrated 3 alleles, with 2 peaks taller than the third, in the FGA locus (chromosome 4). A combination of a triallelic variant and leukemia-associated trisomy 4 explained the finding. STR number variants are rare and clinically inconsequential but can overlap malignancy-associated, clinically significant changes.
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http://dx.doi.org/10.1093/labmed/lmaa022DOI Listing
November 2020

Multi-dimensional analysis identifies an immune signature predicting response to decitabine treatment in elderly patients with AML.

Br J Haematol 2020 03 1;188(5):674-684. Epub 2019 Oct 1.

Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA.

Decitabine is a DNA-hypomethylating agent that has been widely applied for the treatment of acute myeloid leukaemia (AML) patients who are elderly or unfit for intensive therapy. Although effective, the complete response rate to decitabine is only around 30% and the overall survival remains poor. Emerging data support that regulation of DNA methylation is critical to control immune cell development, differentiation and activation. We hypothesize that defining how decitabine influences the immune responses in AML will facilitate the development of novel immune-based leukaemia therapeutics. Here, we performed phenotypic and functional immune analysis on clinical samples from AML patients receiving decitabine treatment and demonstrated a significant impact of decitabine on the immune system. T-cell expression of inhibitory molecules was upregulated and the ability of CD8 T cells to produce cytokines was decreased upon decitabine treatment. Importantly, in an unbiased comprehensive analysis, we identified a unique immune signature containing a cluster of key immune markers that clearly separate patients who achieved complete remission after decitabine from those who failed to do so. Therefore, this immune signature has a strong predictive value for clinical response. Collectively, our study suggests that immune-based analyses may predict clinical response to decitabine and provide a therapeutic strategy to improve the treatment of AML.
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http://dx.doi.org/10.1111/bjh.16228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065206PMC
March 2020

Comparison of High Doses of Total Body Irradiation in Myeloablative Conditioning before Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2019 12 29;25(12):2398-2407. Epub 2019 Aug 29.

Blood & Marrow Transplantation Program, Division of Hematology/Oncology, Department of Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, Maryland.

Malignancy relapse is the most common cause of treatment failure among recipients of hematopoietic cell transplantation (HCT). Conditioning dose intensity can reduce disease relapse but is offset by toxicities. Improvements in radiotherapy techniques and supportive care may translate to better outcomes with higher irradiation doses in the modern era. This study compares outcomes of recipients of increasing doses of high-dose total body irradiation (TBI) divided into intermediate high dose (IH; 13-13.75 Gy) and high dose (HD; 14 Gy) with standard dose (SD; 12 Gy) with cyclophosphamide. A total of 2721 patients ages 18 to 60 years with hematologic malignancies receiving HCT from 2001 to 2013 were included. Cumulative incidences of nonrelapse mortality (NRM) at 5 years were 28% (95% confidence interval [CI], 25% to 30%), 32% (95% CI, 29% to 36%), and 34% (95% CI, 28% to 39%) for SD, IH, and HD, respectively (P = .02). Patients receiving IH-TBI had a 25% higher risk of NRM compared with those receiving SD-TBI (12 Gy) (P = .007). Corresponding cumulative incidences of relapse were 36% (95% CI, 34% to 38%), 32% (95% CI, 29% to 36%), and 26% (95% CI, 21% to 31%; P = .001). Hazard ratios for mortality compared with SD were 1.06 (95% CI, .94 to 1.19; P = .36) for IH and .89 (95% CI, .76 to 1.05; P = .17) for HD. The study demonstrates that despite improvements in supportive care, myeloablative conditioning using higher doses of TBI (with cyclophosphamide) leads to worse NRM and offers no survival benefit over SD, despite reducing disease relapse.
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http://dx.doi.org/10.1016/j.bbmt.2019.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304318PMC
December 2019

Association of Antiepileptic Medications with Outcomes after Allogeneic Hematopoietic Cell Transplantation with Busulfan/Cyclophosphamide Conditioning.

Biol Blood Marrow Transplant 2019 07 11;25(7):1424-1431. Epub 2019 Mar 11.

Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington, Seattle, WA, USA.

High-dose busulfan (BU) followed by high-dose cyclophosphamide (CY) before allogeneic hematopoietic cell transplantation (HCT) has long been used as treatment for hematologic malignancies. Administration of phenytoin or newer alternative antiepileptic medications (AEMs) prevents seizures caused by BU. Phenytoin induces enzymes that increase exposure to active CY metabolites in vivo, whereas alternative AEMs do not have this effect. Lower exposure to active CY metabolites with the use of alternative AEMs could decrease the risk of toxicity but might increase the risk of recurrent malignancy after HCT. Previous studies have not determined whether outcomes with alternative AEMs differ from those with phenytoin in patients treated with BU/CY before allogeneic HCT. We studied a cohort of 2155 patients, including 1460 treated with phenytoin and 695 treated with alternative AEMs, who received BU/CY before allogeneic HCT between 2004 and 2014. We found no differences suggesting decreased overall survival or relapse-free survival or increased risks of relapse, nonrelapse mortality, acute or chronic graft-versus-host disease, or regimen-related toxicity associated with the use of alternative AEMs compared with phenytoin. The risk of dialysis was lower in the alternative AEM group than in the phenytoin group. Alternative AEMs are safe for prevention of seizures after BU administration and can avoid the undesirable toxicities and drug interactions caused by phenytoin.
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http://dx.doi.org/10.1016/j.bbmt.2019.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615968PMC
July 2019

Dendritic Cell Regulation of Graft-Vs.-Host Disease: Immunostimulation and Tolerance.

Front Immunol 2019 1;10:93. Epub 2019 Feb 1.

Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, United States.

Graft-vs.-host disease (GVHD) remains a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Significant progresses have been made in defining the dichotomous role of dendritic cells (DCs) in the development of GVHD. Host-derived DCs are important to elicit allogeneic T cell responses, whereas certain donor-types of DCs derived from newly engrafted hematopoietic stem/progenitor cells (HSPCs) can amply this graft-vs.-host reaction. In contrast, some DCs also play non-redundant roles in mediating immune tolerance. They induce apoptotic deletion of host-reactive donor T cells while promoting expansion and function of regulatory T cells (Treg). Unfortunately, this tolerogenic effect of DCs is impaired during GVHD. Severe GVHD in patients subject to allo-HSCT is associated with significantly decreased number of circulating peripheral blood DCs during engraftment. Existing studies reveal that GVHD causes delayed reconstitution of donor DCs from engrafted HSPCs, impairs the antigen presentation function of newly generated DCs and reduces the capacity of DCs to regulate Treg. The present review will discuss the importance of DCs in alloimmunity and the mechanism underlying DC reconstitution after allo-HSCT.
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http://dx.doi.org/10.3389/fimmu.2019.00093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367268PMC
January 2020

EomesT-bet CD8 T Cells Are Functionally Impaired and Are Associated with Poor Clinical Outcome in Patients with Acute Myeloid Leukemia.

Cancer Res 2019 04 1;79(7):1635-1645. Epub 2019 Feb 1.

Penn State Cancer Institute, Penn State University College of Medicine, Hershey, Pennsylvania.

Acute myeloid leukemia (AML) is a devastating blood cancer with poor prognosis. Immunotherapy targeting inhibitory pathways to unleash the antileukemia T-cell response is a promising strategy for the treatment of leukemia, but we must first understand the underlying molecular mechanisms. Eomesodermin (Eomes) and T-bet are both T-box transcription factors that regulate CD8 T-cell responses in a context-specific manner. Here, we examined the role of these transcription factors in CD8 T-cell immunity in AML patients. We report that the frequency of EomesT-bet CD8 T cells increased in newly diagnosed AML. This cell subset produced fewer cytokines and displayed reduced killing capacity, whereas depletion of Eomes by siRNA reversed these functional defects. Furthermore, Eomes bound the promoter of T-cell immunoglobulin and ITIM domain (TIGIT) and positively regulated the expression of this inhibitory receptor on patient-derived T cells. A high frequency of EomesT-bet CD8 T cells was associated with poor response to induction chemotherapy and shorter overall survival in AML patients. These findings have significant clinical implications as they not only identify a predictive and prognostic biomarker for AML, but they also provide an important target for effective leukemia therapeutics. SIGNIFICANCE: These findings reveal that a high frequency of EomesT-bet CD8 T cells predicts poor clinical outcome in AML and that targeting Eomes may provide a therapeutic benefit against AML.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3107DOI Listing
April 2019

The Hematopoietic Cell Transplant Comorbidity Index predicts survival after allogeneic transplant for nonmalignant diseases.

Blood 2019 02 13;133(7):754-762. Epub 2018 Dec 13.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.

Despite improvements, mortality after allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases remains a significant problem. We evaluated whether pre-HCT conditions defined by the HCT Comorbidity Index (HCT-CI) predict probability of posttransplant survival. Using the Center for International Blood and Marrow Transplant Research database, we identified 4083 patients with nonmalignant diseases transplanted between 2007 and 2014. Primary outcome was overall survival (OS) using the Kaplan-Meier method. Hazard ratios (HRs) were estimated by multivariable Cox regression models. Increasing HCT-CI scores translated to decreased 2-year OS of 82.7%, 80.3%, 74%, and 55.8% for patients with HCT-CI scores of 0, 1 to 2, 3 to 4, and ≥5, respectively, regardless of conditioning intensity. HCT-CI scores of 1 to 2 did not differ relative to scores of 0 (HR, 1.12 [95% CI, 0.93-1.34]), but HCT-CI of 3 to 4 and ≥5 posed significantly greater risks of mortality (HR, 1.33 [95% CI, 1.09-1.63]; and HR, 2.31 [95% CI, 1.79-2.96], respectively). The effect of HCT-CI differed by disease indication. Patients with acquired aplastic anemia, primary immune deficiencies, and congenital bone marrow failure syndromes with scores ≥3 had increased risk of death after HCT. However, higher HCT-CI scores among hemoglobinopathy patients did not increase mortality risk. In conclusion, this is the largest study to date reporting on patients with nonmalignant diseases demonstrating HCT-CI scores ≥3 that had inferior survival after HCT, except for patients with hemoglobinopathies. Our findings suggest that using the HCT-CI score, in addition to disease-specific factors, could be useful when developing treatment plans for nonmalignant diseases.
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http://dx.doi.org/10.1182/blood-2018-09-876284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376282PMC
February 2019

Effect of Conditioning Regimen Dose Reduction in Obese Patients Undergoing Autologous Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2019 03 10;25(3):480-487. Epub 2018 Nov 10.

Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Data are limited on whether to adjust high-dose chemotherapy before autologous hematopoietic cell transplant (autoHCT) in obese patients. This study explores the effects of dose adjustment on the outcomes of obese patients, defined as body mass index (BMI) ≥ 30 kg/m. Dose adjustment was defined as a reduction in standard dosing ≥20%, based on ideal, reported dosing and actual weights. We included 2 groups of US patients who had received autoHCT between 2008 and 2014. Specifically, we included patients with multiple myeloma (MM, n = 1696) treated with high-dose melphalan and patients with Hodgkin or non-Hodgkin lymphomas (n = 781) who received carmustine, etoposide, cytarabine, and melphalan conditioning. Chemotherapy dose was adjusted in 1324 patients (78%) with MM and 608 patients (78%) with lymphoma. Age, sex, BMI, race, performance score, comorbidity index, and disease features (stage at diagnosis, disease status, and time to transplant) were similar between dose groups. In multivariate analyses for MM, adjusting for melphalan dose and for center effect had no impact on overall survival (P = .894) and treatment-related mortality (TRM) (P = .62), progression (P = .12), and progression-free survival (PFS; P = .178). In multivariate analyses for lymphoma, adjusting chemotherapy doses did not affect survival (P = .176), TRM (P = .802), relapse (P = .633), or PFS (P = .812). No center effect was observed in lymphoma. This study demonstrates that adjusting chemotherapy dose before autoHCT in obese patients with MM and lymphoma does not influence mortality. These results do not support adjusting chemotherapy dose in this population.
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http://dx.doi.org/10.1016/j.bbmt.2018.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445718PMC
March 2019

VISTA is highly expressed on MDSCs and mediates an inhibition of T cell response in patients with AML.

Oncoimmunology 2018;7(9):e1469594. Epub 2018 Jul 11.

Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA.

Treatment of acute myeloid leukemia (AML) remains challenging. Enhancement of anti-tumor responses by blocking negative immune regulators is a promising strategy for novel effective leukemia therapeutics. V-domain Ig suppressor of T-cell activation (VISTA) is a recently defined negative regulator mediating immune evasion in cancer. To investigate the effect of VISTA on anti-leukemia immune response in AML, we initiated a study using clinical samples collected from AML patients. Here we report that VISTA is highly expressed on myeloid-derived suppressor cells (MDSCs) in the peripheral blood of AML patients. Both the frequency and intensity of VISTA expression on MDSCs are significantly higher in newly diagnosed AML than in healthy controls. Importantly knockdown of VISTA by specific siRNA potently reduced the MDSCs-mediated inhibition of CD8 T cell activity in AML, suggesting a suppressive effect of VISTA on anti-leukemia T cell response. Furthermore, we observed a strong positive association between MDSC expression of VISTA and T cell expression of PD-1 in AML. These results support the strategy of VISTA-targeted treatment for AML and underscore the strong potential for combined blockade of VISTA and PD-1 pathways in effective leukemia control.
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http://dx.doi.org/10.1080/2162402X.2018.1469594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140587PMC
July 2018

Comparison of pediatric allogeneic transplant outcomes using myeloablative busulfan with cyclophosphamide or fludarabine.

Blood Adv 2018 06;2(11):1198-1206

Mount Sinai Medical Center, New York, NY.

Busulfan combined with cyclophosphamide (BuCy) has long been considered a standard myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (HCT), including both nonmalignant conditions and myeloid diseases. Substituting fludarabine for cyclophosphamide (BuFlu) to reduce toxicity without an increase in relapse has been increasingly performed in children, but without comparison with BuCy. We retrospectively analyzed 1781 children transplanted from 2008 to 2014 to compare the effectiveness of BuCy with BuFlu. Nonmalignant and malignant disease populations were analyzed separately. Overall mortality was comparable for children with nonmalignant conditions who received BuFlu or BuCy (relative risk [RR], 1.14, = .52). Lower incidences of sinusoidal obstruction syndrome ( = .04), hemorrhagic cystitis ( = .04), and chronic graft-versus-host disease ( = .02) were observed after BuFlu, but the influence of the conditioning regimen could not be assessed by multivariate analysis because of the low frequency of these complications. Children transplanted for malignancies were more likely to receive BuFlu if they had higher hematopoietic cell transplantation-comorbidity index scores ( < .001) or their donor was unrelated and HLA-mismatched ( = .004). Nevertheless, there were no differences in transplant toxicities and comparable transplant-related mortality (RR, 1.2; = .46), relapse (RR, 1.2; = .15), and treatment failure (RR, 1.2; = .12). BuFlu was associated with higher overall mortality (RR, 1.4; = .008) related to inferior postrelapse survival ( = .001). Our findings demonstrated that outcomes after BuFlu are similar to those for BuCy for children, but for unclear reasons, those receiving BuFlu for malignancy may be at risk for shorter postrelapse survival.
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http://dx.doi.org/10.1182/bloodadvances.2018016956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998928PMC
June 2018

Clofarabine followed by haploidentical stem cell transplant using fludarabine, busulfan, and total-body irradiation with post-transplant cyclophosphamide in non-remission AML.

Int J Hematol 2018 Sep 14;108(3):348-350. Epub 2018 Mar 14.

Department of Medicine, Division of Hematology/Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.

Approximately 30-40% of patients with acute myeloid leukemia (AML) experience induction failures. In these patients who do not achieve remission with two cycles of standard induction therapies, the probability of achieving remission with subsequent inductions is very limited. Hematopoietic stem cell transplantation (HSCT) is the only curative option for these patients, but high relapse rate and transplant-related mortality often preclude them to proceed to transplant. Thus, AML not in remission at time of HSCT remains a huge unmet need in current HSCT practice, particularly if the patient does not have an HLA-matched donor identified by the time of two induction failures. We used clofarabine cytoreduction immediately followed by fludarabine (Flu) and busulfan (Bu) × 3 with total-body irradiation (TBI) conditioning (Flu/Bu3/TBI) for haploidentical peripheral blood stem cell transplant with post-transplant cyclophosphamide for two cases of refractory AML with a very high tumor burden at transplant and achieved complete remission by day + 30 in both cases.
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http://dx.doi.org/10.1007/s12185-018-2431-5DOI Listing
September 2018

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma.

N Engl J Med 2018 01;378(1):35-47

From the Duke University Medical Center (K.M.S., O.C., E.W.S.C.) and RTI International (D.W.), Durham, and Rho Federal Systems Division, Chapel Hill (L.K.-E., A.P., B.E., S.C.) - all in North Carolina; National Institute of Allergy and Infectious Diseases, Bethesda, MD (E.A.G., B.W., L.M.G., J.S.G.); Colorado Blood Cancer Institute, Denver (P.A.M., R.A.N.); University of Texas McGovern Medical School (M.D.M.) and M.D. Anderson Cancer Center (C.H.) - both in Houston; Vanderbilt University, Nashville (L.J.C., K.P.); University of Michigan, Ann Arbor (D.K., J.R.S.); Case Western Reserve University and University Hospitals, Cleveland (R.J.F.); University of Alabama, Birmingham (S.M.); Boston University, Boston (R.W.S.); University of Virginia, Charlottesville (K.B.); University of Washington (M.H.W., D.E.F.) and the Fred Hutchinson Cancer Research Center (G.E.G., S.H.) - both in Seattle; University of California, Los Angeles, Los Angeles (J.G., S.K., D.E.F.); City of Hope National Medical Center, Duarte, CA (S.F.); Medical University of South Carolina, Charleston (R.M.S.); Mayo Clinic, Scottsdale, AZ (L.G.); University of Calgary, Calgary, AB, Canada (J.S., S.L.); Washington University, St. Louis (R.B.); Medical College of Wisconsin, Milwaukee (M.E.C., C.K.-T.); Ottawa Hospital Research Institute, Ottawa (C.B.); University of Pittsburgh, Pittsburgh (T.M., R.T.D.); and University of Toledo Medical Center, Toledo, OH (M.B.K.).

Background: Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma.

Methods: We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score.

Results: In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group.

Conclusions: Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846574PMC
http://dx.doi.org/10.1056/nejmoa1703327DOI Listing
January 2018

Hematopoietic stem cell transplantation in the era of molecular targeted therapy.

Authors:
Shin Mineishi

Rinsho Ketsueki 2017;58(10):2135-2140

Blood and Marrow Transplant Program, Penn State Hershey Cancer Institute.

Recent developments in the field of molecular targeted therapy are certainly remarkable. However, the role of hematopoietic stem cell transplantation (HSCT) cannot be the same in this trend of targeted therapy. In the past, HSCT was the sole and ultimate treatment for refractory hematological malignancies, mainly because the conditioning regimens were strong and administering any additional therapy was impossible. In recent years, the conditioning regimens have become less intensive, thus enabling the use of additional therapies post-transplantation. In this review, we have discussed the use of each targeted therapy, such as TKIs for Philadelphia chromosome positive disease, Flt3 inhibitors, checkpoint inhibitors, monoclonal antibodies, and hypomethylating agents, in the context of using them with HSCT. Furthermore, we have discussed the importance of the intensity of chemotherapy and conditioning for HSCT and whether the depth of remission and the time of achieving deep remission are important. MRD tests can help to further delineate this point. Molecular targeted therapy will be more prevalent in the near future in the treatment of hematological malignancies where each new agent may impact the GVHD/GVL effect. Thus, clinical trials in the next decade will mostly focus on the role of HSCT and on the methods of combining it with targeted agents to provide the best therapeutic option to patients.
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http://dx.doi.org/10.11406/rinketsu.58.2135DOI Listing
December 2017

PD-1 blockade for relapsed lymphoma post-allogeneic hematopoietic cell transplant: high response rate but frequent GVHD.

Blood 2017 07 3;130(2):221-228. Epub 2017 May 3.

Division of Hematology, The Ohio State University, Columbus, OH.

Given the limited treatment options for relapsed lymphoma post-allogeneic hematopoietic cell transplantation (post-allo-HCT) and the success of programmed death 1 (PD-1) blockade in classical Hodgkin lymphoma (cHL) patients, anti-PD-1 monoclonal antibodies (mAbs) are increasingly being used off-label after allo-HCT. To characterize the safety and efficacy of PD-1 blockade in this setting, we conducted a multicenter retrospective analysis of 31 lymphoma patients receiving anti-PD-1 mAbs for relapse post-allo-HCT. Twenty-nine (94%) patients had cHL and 27 had ≥1 salvage therapy post-allo-HCT and prior to anti-PD-1 treatment. Median follow-up was 428 days (range, 133-833) after the first dose of anti-PD-1. Overall response rate was 77% (15 complete responses and 8 partial responses) in 30 evaluable patients. At last follow-up, 11 of 31 patients progressed and 21 of 31 (68%) remain alive, with 8 (26%) deaths related to new-onset graft-versus-host disease (GVHD) after anti-PD-1. Seventeen (55%) patients developed treatment-emergent GVHD after initiation of anti-PD-1 (6 acute, 4 overlap, and 7 chronic), with onset after a median of 1, 2, and 2 doses, respectively. GVHD severity was grade III-IV acute or severe chronic in 9 patients. Only 2 of these 17 patients achieved complete response to GVHD treatment, and 14 of 17 required ≥2 systemic therapies. In conclusion, PD-1 blockade in relapsed cHL allo-HCT patients appears to be highly efficacious but frequently complicated by rapid onset of severe and treatment-refractory GVHD. PD-1 blockade post-allo-HCT should be studied further but cannot be recommended for routine use outside of a clinical trial.
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http://dx.doi.org/10.1182/blood-2017-01-761346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510790PMC
July 2017

Late-Onset Cerebral Toxoplasmosis After Allogeneic Hematopoietic Stem Cell Transplantation.

Am J Case Rep 2017 Mar 10;18:246-250. Epub 2017 Mar 10.

Blood and Marrow Transplantation and Cellular Therapy Program, University of Alabama at Birmingham, Birmingham, AL, USA.

BACKGROUND Toxoplasmosis is an uncommon but potentially fatal complication following allogeneic hematopoietic stem cell transplantation (HCT). Post-transplant toxoplasmosis is often a reactivation of prior infection and typically occurs within the first 6 months of transplant. Herein, we report that cerebral toxoplasmosis may occur 22 months after allogeneic hematopoietic stem cell transplantation. CASE REPORT We describe a case of cerebral toxoplasmosis that occurred 22 months after an allogeneic HCT while the patient was on aerosolized pentamidine for Pneumocystis jiroveci pneumonia (PCP) prophylaxis. The disease was only diagnosed after brain biopsy because of atypical MRI appearance of the cerebral lesion and negative Toxoplasma gondii IgG antibody test result in the cerebrospinal fluid (CSF). The patient received pyrimethamine and sulfadiazine treatment, with dramatic improvement after several months. The patient is alive 2 years after infection diagnosis, with no evidence of disease and is off Toxoplasma prophylaxis. CONCLUSIONS Cerebral toxoplasmosis can occur late after allogeneic HCT while patients are on immunosuppression therapy, with atypical features on imaging studies and negative Toxoplasma gondii IgG antibody test result in the CSF. Pre-transplant serologic screening for T. gondii antibodies in allogeneic transplant candidates is warranted. Brain biopsy can be a helpful diagnostic tool for cerebral lesions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358837PMC
http://dx.doi.org/10.12659/ajcr.899687DOI Listing
March 2017

Late-Onset Cerebral Toxoplasmosis After Allogeneic Hematopoietic Stem Cell Transplantation.

Am J Case Rep 2017 Mar 10;18:246-250. Epub 2017 Mar 10.

Blood and Marrow Transplantation and Cellular Therapy Program, University of Alabama at Birmingham, Birmingham, AL, USA.

BACKGROUND Toxoplasmosis is an uncommon but potentially fatal complication following allogeneic hematopoietic stem cell transplantation (HCT). Post-transplant toxoplasmosis is often a reactivation of prior infection and typically occurs within the first 6 months of transplant. Herein, we report that cerebral toxoplasmosis may occur 22 months after allogeneic hematopoietic stem cell transplantation. CASE REPORT We describe a case of cerebral toxoplasmosis that occurred 22 months after an allogeneic HCT while the patient was on aerosolized pentamidine for Pneumocystis jiroveci pneumonia (PCP) prophylaxis. The disease was only diagnosed after brain biopsy because of atypical MRI appearance of the cerebral lesion and negative Toxoplasma gondii IgG antibody test result in the cerebrospinal fluid (CSF). The patient received pyrimethamine and sulfadiazine treatment, with dramatic improvement after several months. The patient is alive 2 years after infection diagnosis, with no evidence of disease and is off Toxoplasma prophylaxis. CONCLUSIONS Cerebral toxoplasmosis can occur late after allogeneic HCT while patients are on immunosuppression therapy, with atypical features on imaging studies and negative Toxoplasma gondii IgG antibody test result in the CSF. Pre-transplant serologic screening for T. gondii antibodies in allogeneic transplant candidates is warranted. Brain biopsy can be a helpful diagnostic tool for cerebral lesions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358837PMC
http://dx.doi.org/10.12659/ajcr.899687DOI Listing
March 2017

Late-Onset Cerebral Toxoplasmosis After Allogeneic Hematopoietic Stem Cell Transplantation.

Am J Case Rep 2017 Mar 10;18:246-250. Epub 2017 Mar 10.

Blood and Marrow Transplantation and Cellular Therapy Program, University of Alabama at Birmingham, Birmingham, AL, USA.

BACKGROUND Toxoplasmosis is an uncommon but potentially fatal complication following allogeneic hematopoietic stem cell transplantation (HCT). Post-transplant toxoplasmosis is often a reactivation of prior infection and typically occurs within the first 6 months of transplant. Herein, we report that cerebral toxoplasmosis may occur 22 months after allogeneic hematopoietic stem cell transplantation. CASE REPORT We describe a case of cerebral toxoplasmosis that occurred 22 months after an allogeneic HCT while the patient was on aerosolized pentamidine for Pneumocystis jiroveci pneumonia (PCP) prophylaxis. The disease was only diagnosed after brain biopsy because of atypical MRI appearance of the cerebral lesion and negative Toxoplasma gondii IgG antibody test result in the cerebrospinal fluid (CSF). The patient received pyrimethamine and sulfadiazine treatment, with dramatic improvement after several months. The patient is alive 2 years after infection diagnosis, with no evidence of disease and is off Toxoplasma prophylaxis. CONCLUSIONS Cerebral toxoplasmosis can occur late after allogeneic HCT while patients are on immunosuppression therapy, with atypical features on imaging studies and negative Toxoplasma gondii IgG antibody test result in the CSF. Pre-transplant serologic screening for T. gondii antibodies in allogeneic transplant candidates is warranted. Brain biopsy can be a helpful diagnostic tool for cerebral lesions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358837PMC
http://dx.doi.org/10.12659/ajcr.899687DOI Listing
March 2017

Update on stem cell transplantation for acute leukemias.

Authors:
Shin Mineishi

Rinsho Ketsueki 2016 ;57(10):2218-2223

Blood and Marrow Transplant Program, Penn State Hershey Medical Center.

The treatment strategies for acute leukemia are undergoing very rapid change. Particularly for last 10 years, due to the rapid development of molecular targeted therapy and cell/gene therapies, the role of HSCT in the treatment scheme of acute leukemia has been changing. In the author's view, these recent changes should secure the role of HSCT in the comprehensive treatment scheme of acute leukemia. By appropriately combining the new agents with HSCT, therapy for acute leukemia is anticipated to become more effective. HSCT will provide the centerpiece for the treatment scheme, by setting up the "platform" for further interventions. Keeping these changes in mind, transplant physicians should now be exploring new areas of research such as interactions between these new agents and GVHD/GVL.
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http://dx.doi.org/10.11406/rinketsu.57.2218DOI Listing
February 2017

Intravenous Busulfan-Based Myeloablative Conditioning Regimens Prior to Hematopoietic Cell Transplantation for Hematologic Malignancies.

Biol Blood Marrow Transplant 2016 08 3;22(8):1424-1430. Epub 2016 May 3.

The Ottawa Hospital Blood and Marrow Transplant Program and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Busulfan (Bu)-containing regimens are commonly used in myeloablative conditioning regimens before allogeneic hematopoietic cell transplantation (HCT). Yet, there is considerable variability on how Bu is administered related to frequency (4 times a day [Q6] or daily [Q24]) and combinations with other chemotherapeutic agents (cyclophosphamide [Cy] or fludarabine [Flu]). We performed a prospective cohort study of recipients of Bu-based conditioning according to contemporary practices to compare different approaches (BuCy Q6, n = 495; BuFlu Q24, n = 331; BuCy Q24, n = 96; BuFlu Q6, n = 91) in patients with myeloid malignancies between 2009 and 2011. BuFlu Q24 recipients were more likely to be older and tended to have worse performance status and a higher comorbid burden. The cumulative incidences of hepatic veno-occlusive disease (P = .40), idiopathic pneumonia (P = .50), and seizures (P = .50) did not differ across groups. One-year HCT-related mortality ranged from 12% to 16% (P = .80), 3-year relapse incidence ranged from 32% to 36% (P = .80), and 3-year overall survival ranged from 51% to 58% (P = .20) across groups. This study demonstrates that HCT conditioning regimens using i.v. Bu Q6 or Q24 alone or in combination with Cy or Flu have similar outcomes in the myeloablative setting for treatment of myeloid malignancies.
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http://dx.doi.org/10.1016/j.bbmt.2016.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949158PMC
August 2016

Programming of donor T cells using allogeneic δ-like ligand 4-positive dendritic cells to reduce GVHD in mice.

Blood 2016 06 3;127(25):3270-80. Epub 2016 May 3.

Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Department of Microbiology and Immunology, Temple University, Philadelphia, PA;

Alloreactive T cells play a critical role in eliminating hematopoietic malignant cells but are also the mediators of graft-versus-host disease (GVHD), a major complication that subverts the success of allogeneic hematopoietic stem cell transplantation (HSCT). However, induction of alloreactive T cells does not necessarily lead to GVHD. Here we report the development of a cellular programming approach to render alloreactive T cells incapable of causing severe GVHD in both major histocompatibility complex (MHC)-mismatched and MHC-identical but minor histocompatibility antigen-mismatched mouse models. We established a novel platform that produced δ-like ligand 4-positive dendritic cells (Dll4(hi)DCs) from murine bone marrow using Flt3 ligand and Toll-like receptor agonists. Upon allogeneic Dll4(hi)DC stimulation, CD4(+) naïve T cells underwent effector differentiation and produced high levels of interferon γ (IFN-γ) and interleukin-17 in vitro, depending on Dll4 activation of Notch signaling. Following transfer, allogeneic Dll4(hi)DC-induced T cells were unable to mediate severe GVHD but preserved antileukemic activity, significantly improving the survival of leukemic mice undergoing allogeneic HSCT. This effect of Dll4(hi)DC-induced T cells was associated with their impaired expansion in GVHD target tissues. IFN-γ was important for Dll4(hi)DC programming to reduce GVHD toxicities of alloreactive T cells. Absence of T-cell IFN-γ led to improved survival and expansion of Dll4(hi)DC-induced CD4(+) T cells in transplant recipients and caused lethal GVHD. Our findings demonstrate that Dll4(hi)DC programming can overcome GVHD toxicity of donor T cells and produce leukemia-reactive T cells for effective immunotherapy.
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http://dx.doi.org/10.1182/blood-2015-05-644476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920025PMC
June 2016
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