Publications by authors named "Emmanuel Katsanis"

70 Publications

The effects of β and β adrenergic receptor blockade on the exercise-induced mobilization and ex vivo expansion of virus-specific T cells: implications for cellular therapy and the anti-viral immune effects of exercise.

Cell Stress Chaperones 2020 11 10;25(6):993-1012. Epub 2020 Aug 10.

Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX, USA.

The adoptive transfer of donor-derived virus-specific T cells (VSTs) is an effective treatment for infections following allogeneic hematopoietic cell transplantation. Acute exercise mobilizes effector lymphocytes and VSTs to the circulation and augments the ex vivo manufacture of VSTs. This study determined if β adrenergic receptor (AR) signaling precipitated the VST response to acute exercise. Healthy participants (n = 12) completed 30 min of steady-state cycling exercise after ingesting a placebo, a β AR antagonist (nadolol) or a β AR antagonist (bisoprolol). Circulating VSTs to cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus (AdV) antigens were enumerated before and after exercise, and peripheral blood mononuclear cells were cultured with viral peptides for 8 days to expand multi-VSTs. Compared with placebo, nadolol blunted the exercise-induced mobilization of CMV-VSTs (Δ VSTs/100,000 CD3 T cells = 93 ± 104 vs. 22 ± 91 for placebo and nadolol, respectively; p = 0.036), while bisoprolol did not, despite both drugs evoking similar reductions in exercising heart rate and blood pressure. Circulating AdV and EBV VSTs (VSTs/mL blood) only increased after exercise with placebo. Although not significant, nadolol partially mitigated exercise-induced increases in multi-VST expansion, particularly in participants that demonstrated an exercise-induced increase in VST expansion. We conclude that exercise-induced enhancements in VST mobilization and expansion are at least partially β AR mediated, thus highlighting a role for the β AR in targeted therapy for the augmentation of VST immune cell therapeutics in the allogeneic adoptive transfer setting. Moreover, long-term regular exercise may provide additional viral protection in the host through frequent β AR-dependent mobilization and redistribution of VSTs cumulated with each bout of exercise.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12192-020-01136-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591642PMC
November 2020

Bendamustine Conditioning Skews Murine Host DCs Toward Pre-cDC1s and Reduces GvHD Independently of Batf3.

Front Immunol 2020 16;11:1410. Epub 2020 Jul 16.

Department of Immunobiology, University of Arizona, Tucson, AZ, United States.

Graft-versus-host disease (GvHD) remains the second leading cause of death in allogeneic hematopoietic stem cell transplantation recipients, highlighting the need for improved preventative strategies. Our laboratory has previously demonstrated in an experimental bone marrow transplantation (BMT) model that bendamustine combined with total body irradiation (BEN+TBI) is a safer alternative to cyclophosphamide with TBI (CY+TBI). The biological mechanisms of action of BEN have not been fully elucidated and likely involve multiple cell populations. Host dendritic cells (DCs) can prime naïve donor T-cells immediately following transplantation, making host DCs critical for the initiation phase of GvHD. We hypothesized that BEN+TBI conditioning favorably alters host DC composition to reduce GvHD. We demonstrate that host DCs treated with BEN+TBI induce less allogeneic T-cell proliferation than those conditioned with CY+TBI. We further show that BEN+TBI conditioning results in greater total numbers of all host DC subsets but with a more favorable composition compared to CY+TBI with significantly larger proportions of type 1 conventional DCs (cDC1), a highly regulatory DC subset capable of suppressing GvHD. Our studies using recipient Batf3 KO mice indicate that CD8α+ cDC1s are largely dispensable for the reduced GvHD following BEN+TBI conditioning. We found a higher frequency of host pre-cDC1s with BEN+TBI conditioning in both wild-type (WT) and Batf3 KO mice, which was inversely associated with GvHD. Additionally, we observed that BEN treatment results in greater expression of Flt3 receptor (CD135) on host DCs compared to CY, potentially contributing to the skewing of host DCs toward cDC1s. Further, BEN+TBI conditioning results in host cDCs with greater expression of PIR-B, an inhibitory receptor capable of preventing lethal GvHD. We conclude that BEN+TBI is a safer alternative to CY+TBI, resulting in a greater frequency of host pre-cDC1s and limiting GvHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.01410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378358PMC
July 2020

T-Cell Replete Myeloablative Haploidentical Bone Marrow Transplantation Is an Effective Option for Pediatric and Young Adult Patients With High-Risk Hematologic Malignancies.

Front Pediatr 2020 9;8:282. Epub 2020 Jun 9.

The University of Arizona Cancer Center, Tucson, AZ, United States.

Twenty-one pediatric and young adult patients (1.1-24.7 years) with hematologic malignancies underwent myeloablative T-cell replete haploidentical bone marrow transplant (haplo-BMT) between October 2015 to December 2019. Fifty-seven percent of the patients were ethnic or racial minorities. Thirteen patients had B-cell precursor acute lymphoblastic leukemia (B-ALL) with 10 receiving 1,200 cGy fractionated total body irradiation with fludarabine while the remaining 11 patients had targeted dose-busulfan, fludarabine, melphalan conditioning. Graft-vs.-host disease (GvHD) prophylaxis consisted of post-transplant cyclophosphamide (15 patients) or cyclophosphamide and bendamustine (six patients), with all patients receiving tacrolimus and mycophenolate mofetil. Twelve patients were in first or second remission at time of transplant with five in >2nd remission and four with measurable disease. Three patients had failed prior transplants and three CAR-T cell therapies. Only one patient developed primary graft failure but engrafted promptly after a second conditioned T-replete peripheral blood stem cell transplant from the same donor. An absolute neutrophil count of 0.5 × 10/L was achieved at a median time of 16 days post-BMT while platelet engraftment occurred at a median of 30 days. The cumulative incidence of grades III to IV acute GvHD and chronic GvHD was 15.2 and 18.1%, respectively. With a median follow-up of 25.1 months the relapse rate is 17.6% with an overall survival of 84.0% and a progression-free survival of 74.3%. The chronic graft-vs.-host-free relapse-free survival (CRFS) is 58.5% while acute and chronic graft-vs.-host-free relapse-free survival (GRFS) is 50.1%. Myeloablative conditioned T-replete haploidentical BMT is a viable alternative to matched unrelated transplantation for children and young adults with high-risk hematologic malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2020.00282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295947PMC
June 2020

Bendamustine with total body irradiation conditioning yields tolerant T-cells while preserving T-cell-dependent graft-versus-leukemia.

Oncoimmunology 2020 30;9(1):1758011. Epub 2020 Apr 30.

Department of Pediatrics, University of Arizona, Tucson, AZ, USA.

Graft-versus-host disease (GvHD) remains a significant impediment to allogeneic hematopoietic cell transplantation (HCT) success, necessitating studies focused on alleviating GvHD, while preserving the graft-versus-leukemia (GvL) effect. Based on our previous studies showing bendamustine with total body irradiation (BEN-TBI) conditioning reduces GvHD compared to the current clinical standard of care cyclophosphamide (CY)-TBI in a murine MHC-mismatched bone marrow transplantation (BMT) model, this study aimed to evaluate the role and fate of donor T-cells following BEN-TBI conditioning. We demonstrate that BEN-TBI reduces GvHD compared to CY-TBI independently of T regulatory cells (Tregs). BEN-TBI conditioned mice have a smaller proportion and less activated donor T-cells, with lower CD47 expression, early post-transplant, but no sustained phenotypic differences in T-cells. In BEN-TBI conditioned mice, donor T-cells gain tolerance specific to host MHC antigens. Though these T-cells are tolerant to host antigens, we demonstrate that BEN-TBI preserves a T-cell-dependent GvL effect. These findings indicate that BEN-TBI conditioning reduces GvHD without compromising GvL, warranting its further investigation as a potentially safer and more efficacious clinical alternative to CY-TBI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2020.1758011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199810PMC
April 2020

The immunological case for staying active during the COVID-19 pandemic.

Brain Behav Immun 2020 07 18;87:6-7. Epub 2020 Apr 18.

Department of Pediatrics, University of Arizona, Tucson, AZ, USA; Department of Immunobiology, University of Arizona, Tucson, AZ, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2020.04.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165095PMC
July 2020

Systemic β-Adrenergic Receptor Activation Augments the Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells.

Front Immunol 2019 24;10:3082. Epub 2020 Jan 24.

Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX, United States.

TCR-gamma delta (γδ) T-cells are considered important players in the graft-vs.-tumor effect following allogeneic hematopoietic cell transplantation (alloHCT) and have emerged as candidates for adoptive transfer immunotherapy in the treatment of both solid and hematological tumors. Systemic β-adrenergic receptor (β-AR) activation has been shown to mobilize TCR-γδ T-cells to the blood, potentially serving as an adjuvant for alloHCT and TCR-γδ T-cell therapy. We investigated if systemic β-AR activation, using acute dynamic exercise as an experimental model, can increase the mobilization, expansion, and anti-tumor activity of TCR-γδ T-cells isolated from the blood of healthy humans. We also sought to investigate the β-AR subtypes involved, by administering a preferential β-AR antagonist (bisoprolol) and a non-preferential β + β-AR antagonist (nadolol) prior to exercise as part of a randomized placebo controlled cross-over experiment. We found that exercise mobilized TCR-γδ cells to blood and augmented their expansion by ~182% compared to resting blood when stimulated with IL-2 and ZOL for 14-days. Exercise also increased the proportion of CD56+, NKG2D+/CD62L-, CD158a/b/e+ and NKG2A- cells among the expanded TCR-γδ cells, and increased their cytotoxic activity against several tumor target cells (K562, U266, 221.AEH) by 40-60%. Blocking NKG2D on TCR-γδ cells eliminated the augmented cytotoxic effects of exercise against U266 target cells. Furthermore, administering a β + β-AR (nadolol), but not a β-AR (bisoprolol) antagonist prior to exercise abrogated the exercise-induced enhancement in TCR-γδ T-cell mobilization and expansion. Furthermore, nadolol completely abrogated while bisoprolol partially inhibited the exercise-induced increase in the cytotoxic activity of the expanded TCR-γδ T-cells. We conclude that acute systemic β-AR activation in healthy donors markedly augments the mobilization, expansion, and anti-tumor activity of TCR-γδ T-cells and that some of these effects are due to β-AR signaling and phenotypic shifts that promote a dominant activating signal via NKG2D. These findings highlight β-ARs as potential targets to favorably alter the composition of allogeneic peripheral blood stem cell grafts and improve the potency of TCR-γδ T-cell immune cell therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.03082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993603PMC
November 2020

Exercise as a countermeasure for latent viral reactivation during long duration space flight.

FASEB J 2020 02 3;34(2):2869-2881. Epub 2020 Jan 3.

Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX, USA.

Latent viral reactivation is a commonly reported manifestation of immune system dysregulation during spaceflight. As physical fitness and exercise training have been shown to benefit multiple arms of the immune system, we hypothesized that higher levels of preflight physical fitness and/or maintaining fitness during a mission would protect astronauts from latent viral reactivation. Standardized tests of maximal strength, muscular endurance, flexibility, and cardiorespiratory fitness (CRF) were performed in 22 international space station (ISS) crewmembers before and after a ~6-month mission. Reactivation of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and varicella zoster virus (VZV) was determined in crewmembers and ground-based controls before, during, and after spaceflight. Crewmembers with higher CRF before spaceflight had a 29% reduced risk of latent viral reactivation compared to crew with lower CRF. Higher preflight upper body muscular endurance was associated with a 39% reduced risk of viral reactivation, a longer time to viral reactivation, and lower peak viral DNA concentrations, particularly for EBV and VZV. Latent viral reactivation rates were highest in crew with lower preflight CRF and higher levels of CRF deconditioning on return to Earth. We conclude that physical fitness may protect astronauts from latent viral reactivation during long duration spaceflight missions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201902327RDOI Listing
February 2020

Transfusion independence after repeated haploidentical hematopoietic cell transplants in a patient with congenital dyserythropoietic anemia type II and hemosiderosis.

Pediatr Transplant 2019 12 17;23(8):e13587. Epub 2019 Sep 17.

Department of Pediatrics, University of Arizona, Tucson, Arizona.

Matched related or unrelated donor allogeneic HCT has occasionally been applied in patients with severe CDA type II and proven to be curative. We report on the first patient with CDA to undergo haploidentical bone marrow transplantation with PT-CY. A 12-year-old boy with severe hemosiderosis, and a, consequently, disturbed BM microenvironment, developed recurrent graft failures and required salvage with two additional haploidentical HCTs. He achieved complete donor chimerism and transfusion independence after the third HCT. Our case underscores the risks associated with performing haploidentical HCT in older pediatric patients with CDA and severe chronic iron overload.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/petr.13587DOI Listing
December 2019

The Impact of Low-Dose Cranial Boost on the Long-Term Outcomes of Adult Patients with High-Risk Acute Lymphoblastic Leukemia Undergoing Total Body Irradiation and Allogeneic Hematopoietic Stem Cell Transplantation.

Pract Radiat Oncol 2019 May 20;9(3):e283-e289. Epub 2018 Dec 20.

Department of Radiation Oncology, The University of Arizona, Tucson, Arizona; College of Medicine, The University of Arizona, Tucson, Arizona.

Purpose: Total body irradiation (TBI) is an integral part of the conditioning regimen for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic, hematopoietic, cell transplantation (allo-HCT). There are conflicting data in the literature regarding the utility of a cranial irradiation boost in high-risk adult ALL without evidence of preexisting central nervous system (CNS) involvement. This study investigates the posttransplant clinical outcomes of patients with high-risk adult ALL undergoing TBI conditioning for allo-HCT with or without a whole-brain boost, without overt CNS involvement at the time of diagnosis.

Methods And Materials: A retrospective cohort study was conducted using a medical record analysis. We identified 58 patients who were treated between January 1998 and December 2016, and met our preset inclusion criteria of adults (age >18 years old) who carried a pathologically confirmed diagnosis of CNS-negative, high-risk ALL, who underwent hematopoietic stem cell transplantation with TBI conditioning. A multivariate analysis of correlation between patient outcomes and collected categorical variables was assessed with stepwise Cox logistic regression. Survival analyses were assessed using the Kaplan-Meier technique with a log-rank test.

Results: With a median follow-up time of 5.3 years, there was a statistically significant improvement in actuarial 7-year CNS relapse-free survival (100% vs 76.4%; P = .043) in favor of patients undergoing a cranial boost. There was no statistically significant improvement in 7-year progression-free survival (78.3% vs 62.5%; P = .076) or overall survival (49.4% vs 43.5%; P = .921) with versus without a cranial boost. On multivariate analysis, the presence of a cranial boost was the only identified variable with an independent relationship to CNS relapse-free survival.

Conclusions: Adult patients with high-risk, CNS-negative ALL were found to have a statistically significant improvement in CNS relapse-free survival and a trend toward improved progression-free survival with the inclusion of a cranial boost with TBI pretransplant conditioning. Our data indicate that further investigation into the use of cranial boost in this patient population is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prro.2018.12.005DOI Listing
May 2019

Esophageal Varices in Adolescent and Young Adult Males with Acute Lymphocytic Leukemia.

J Adolesc Young Adult Oncol 2019 04 18;8(2):217-220. Epub 2018 Oct 18.

1 Department of Pediatrics, University of Arizona, Tucson, Arizona.

Hepatic late effects are not commonly reported in survivors of childhood leukemia. Four young male patients with acute lymphoblastic leukemia (ALL) were diagnosed with bleeding esophageal varices (EVs) during or shortly after completion of maintenance chemotherapy. EVs were identified from 0 to 60 months after completion of leukemia therapy. All four patients were men between 20 to 24 years old. Hematemesis was the most common presenting symptom. Associated features included splenomegaly, cytopenias, azole therapy, alcohol use, and hepatic iron overload. EVs may be an under-recognized complication of ALL therapy, with adolescent and young adult males at highest risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/jayao.2018.0098DOI Listing
April 2019

Bendamustine with Total Body Irradiation Limits Murine Graft-versus-Host Disease in Part Through Effects on Myeloid-Derived Suppressor Cells.

Biol Blood Marrow Transplant 2019 03 13;25(3):405-416. Epub 2018 Oct 13.

Department of Pediatrics, University of Arizona, Tucson, Arizona; Department of Immunobiology, University of Arizona, Tucson, Arizona; Department of Medicine, University of Arizona, Tucson, Arizona; Department of Pathology, University of Arizona, Tucson, Arizona; University of Arizona Cancer Center, Tucson, Arizona. Electronic address:

Graft-versus-host disease (GVHD) remains a significant challenge in allogeneic hematopoietic cell transplantation (HCT). An underinvestigated strategy to reduce GVHD is the modification of the preparative conditioning regimen. In the present study, we aimed to evaluate GVHD associated with bendamustine (BEN) conditioning in conjunction with total body irradiation (TBI) as an alternative to the standard myeloablative regimen of cyclophosphamide (CY) and TBI. We demonstrate that BEN-TBI conditioning, although facilitating complete donor chimerism, results in significantly less GVHD compared with CY-TBI. In BEN-TBI-conditioned mice, suppressive CD11bGr-1 myeloid cells are increased in the blood, bone marrow, spleen, and intestines. When Gr-1 cells are depleted before transplantation, the beneficial effects of BEN-TBI are partially lost. Alternatively, administration of granulocyte colony-stimulating factor, which promotes CD11bGr-1 myeloid cell expansion, is associated with a trend toward increased survival in BEN-TBI-conditioned mice. These findings indicate a potential role of myeloid-derived suppressor cells in the mechanism by which BEN allows engraftment with reduced GVHD. BEN-TBI conditioning may present a safer alternative to CY-TBI conditioning for allogeneic HCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2018.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571287PMC
March 2019

Supernumerary Incisors in CB6F1 Mice Conditioned with Chemotherapy and Total Body Irradiation before Bone Marrow Transplantation.

Comp Med 2018 10 12;68(5):349-352. Epub 2018 Sep 12.

University Animal Care, University of Arizona, Tucson, Arizona, USA.

Multiple adult female CB6F1 mice presented with supernumerary incisors after preconditioning with chemotherapy and total body irradiation for bone marrow transplantation (BMT). Mice received nonmyeloablative total body irradiation (3 Gy) and either cyclophosphamide or bendamustine, followed by BMT and posttransplantation cyclophosphamide or bendamustine. Here we describe the clinical presentation, μCT findings, and histopathologic evaluation of the affected mice. These analyses confirmed the gross diagnosis and revealed details of the abnormal tooth morphology. We surmise that the combination of total body irradiation and chemotherapy resulted in the abnormal formation of supernumerary incisors. Supernumerary teeth should be considered as a potential confounding factor in tracking weight loss after BMT. These conditions can be managed to allow animals to reach their intended scientific endpoint.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.30802/AALAS-CM-18-000043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200027PMC
October 2018

β-Adrenergic receptor signaling mediates the preferential mobilization of differentiated subsets of CD8+ T-cells, NK-cells and non-classical monocytes in response to acute exercise in humans.

Brain Behav Immun 2018 11 30;74:143-153. Epub 2018 Aug 30.

Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, 3875 Holman Street, Houston, TX, USA; Department of Nutritional Sciences, University of Arizona, Tucson, AZ, USA; Department of Pediatrics, University of Arizona, Tucson, AZ, USA; Department of Immunobiology, University of Arizona, Tucson, AZ, USA; Department of Behavioral Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Acute exercise preferentially mobilizes cytotoxic T-cells, NK-cells and non-classical monocytes to the bloodstream under the influence of hemodynamic forces and/or β-adrenergic receptor (β-AR) signaling. However, the relative contribution of these mechanisms to the redeployment of the most exercise-responsive cell types is largely unknown. We determined the lymphocyte and monocyte subtypes mobilized to blood during exercise via β-AR signaling whilst controlling for β-AR mediated reductions in hemodynamic forces. In a randomized, double blind, complete cross-over design, 14 healthy cyclists exercised for 30-minutes at +10% of blood lactate threshold after ingesting: (1) a placebo, (2) a β-preferential antagonist (10 mg bisoprolol), or (2) a non-preferential β + β-antagonist (80 mg nadolol) across three trials separated by >7-days. Bisoprolol was administered to reduce hemodynamic forces (heart rate and blood pressure) during exercise to levels comparable with nadolol but without blocking β-ARs. The mobilization of total NK-cells, terminally differentiated (CD57+) NK-cells, central memory, effector memory and CD45RA+ effector memory CD8+ T-cells; non-classical monocytes; and γδ T-cells were significantly blunted or abrogated under nadolol compared to both bisoprolol and placebo, indicating that the exercise-induced mobilization of these cell types to the blood is largely influenced by β-AR signaling. Nadolol failed to inhibit the mobilization of classical monocytes, CD4+ T-cells (and their subsets) or naïve CD8+ T-cells, indicating that these cell types are mobilized with exercise independently of the β-AR. We conclude that the preferential mobilization of NK-cells, non-classical monocytes and differentiated subsets of CD8+ T-cells with exercise is largely dependent on catecholamine signaling through the β-AR. These findings provide mechanistic insights by which distinct lymphocyte and monocyte subtypes are preferentially mobilized to protect the host from anticipated injury or infection in response to an acute stress response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2018.08.017DOI Listing
November 2018

Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide/Bendamustine in Pediatric and Young Adult Patients with Hematologic Malignancies.

Biol Blood Marrow Transplant 2018 10 14;24(10):2034-2039. Epub 2018 Jun 14.

Department of Pediatrics, University of Arizona, Tucson, Arizona; University of Arizona Cancer Center, Tucson, Arizona; University of Arizona, Arizona and Banner University Medical Center, Tucson, Arizona.

More than half of patients undergoing hematopoietic cell transplantation at our institution are ethnic or racial minorities, making the search for matched unrelated donors more challenging. Since the introduction of haploidentical bone marrow transplant (haplo-BMT) into our pediatric BMT program in 2015, 69.2% of recipients have been minorities. Herein, we describe our experience with the first 13 pediatric and young adult patients with hematologic malignancies who have undergone T cell-replete haplo-BMT after myeloablative conditioning (MAC) at our institution. We have previously documented that in experimental haplo-BMT, post-transplant bendamustine (PT-BEN) is at least as effective as post-transplant cyclophosphamide (PT-CY) against graft-versus-host disease (GVHD) and elicits superior graft-versus-leukemia (GVL) effects. We report on, for the first time in humans, 4 patients treated with PT-CY and PT-BEN after haplo-BMT as part of our ongoing institutional phase I/II study (NCT02996773). The remaining 9 patients reviewed in this report received PT-CY. Our findings indicate that MAC haplo-BMT is well tolerated by children and young adults with advanced hematologic malignancies with no observed nonrelapse mortality or grades III to IV GVHD. All patients who underwent haplo-BMT remain alive and disease-free with a median follow-up of 15.6 months (range, 1.5 to 31.2). Preliminary findings from our ongoing clinical trial demonstrate that partial substitution of PT-BEN for PT-CY is feasible and safe after haplo-BMT as an immune modulatory strategy to alleviate GVHD and potentially more effectively preserve GVL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2018.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556327PMC
October 2018

Successful resolution of hyperammonemia following hematopoietic cell transplantation with directed treatment of Ureaplasma parvum infection.

Transpl Infect Dis 2018 Apr 12;20(2):e12839. Epub 2018 Feb 12.

Department of Pediatrics, University of Arizona, Tucson, AZ, USA.

Hyperammonemia following hematopoietic cell transplantation (HCT) has been characterized as idiopathic and is associated with a very high mortality. A causal relationship between Ureaplasma infection and hyperammonemia in immunocompromised lung transplant recipients has recently been described. We document the first case of hyperammonemia following HCT associated with Ureaplasma parvum. The initiation of appropriate antibiotics resulted in rapid resolution of hyperammonemic encephalopathy and eradication of the implicating organism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tid.12839DOI Listing
April 2018

Pak2 regulates myeloid-derived suppressor cell development in mice.

Blood Adv 2017 Oct 10;1(22):1923-1933. Epub 2017 Oct 10.

Department of Pediatrics, Steele Children's Research Center.

Myeloid-derived suppressor cells (MDSCs) are CD11bGr1 cells that induce T-cell hyporesponsiveness, thus impairing antitumor immunity. We have previously reported that disruption of Pak2, a member of the p21-activated kinases (Paks), in hematopoietic stem/progenitor cells (HSPCs) induces myeloid lineage skewing and expansion of CD11bGr1 cells in mice. In this study, we confirmed that CD11bGr1 cells suppressed T-cell proliferation, consistent with an MDSC phenotype. Loss of Pak2 function in HSPCs led to (1) increased hematopoietic progenitor cell sensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, (2) increased MDSC proliferation, (3) decreased MDSC sensitivity to both intrinsic and Fas-Fas ligand-mediated apoptosis, and (4) promotion of MDSCs by Pak2-deficient CD4 T cells that produced more interferon γ, tumor necrosis factor α, and GM-CSF. Pak2 disruption activated STAT5 while downregulating the expression of , a well-described myeloid transcription factor. Together, our data reveal a previously unrecognized role of Pak2 in regulating MDSC development via both cell-intrinsic and extrinsic mechanisms. Our findings have potential translational implications, as the efficacy of targeting Paks in cancer therapeutics may be undermined by tumor escape from immune control and/or acceleration of tumorigenesis through MDSC expansion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2017007435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728145PMC
October 2017

Potential niche indications for blinatumomab as a bridge to hematopoietic cell transplantation.

Bone Marrow Transplant 2017 12 18;52(12):1671-1673. Epub 2017 Sep 18.

Department of Pediatrics, University of Arizona, Tucson, Arizona, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/bmt.2017.186DOI Listing
December 2017

Allogeneic Transplant in ELANE and MEFV Mutation Positive Severe Cyclic Neutropenia: Review of Prognostic Factors for Secondary Severe Events.

Case Rep Hematol 2017 18;2017:5375793. Epub 2017 Jan 18.

Department of Pediatrics, University of Arizona, Tucson, AZ, USA; Division of Hematology and Oncology, University of Arizona, Tucson, AZ, USA.

Cyclic neutropenia (CyN) is a rare autosomal dominant inherited disorder due to the mutation ELANE primarily affecting bone marrow stem cells and is characterized by recurrent neutropenia every 2 to 4 weeks. Symptoms vary from benign to severe, including death. Postulations on the cause of wide spectrum in symptom presentation include the possibility of other genetic mutations, such as MEFV. Recommended treatment for CyN is G-CSF to keep ANC higher to minimize risk of infection. A 25-year-old male diagnosed with CyN, on G-CSF but worsening quality of life. Pretransplant investigations revealed ELANE mutation positive severe CyN along with familial Mediterranean fever (MEFV) mutation. Bone marrow transplantation as treatment for dual mutation (ELANE and MEFV mutation) positive severe CyN. BMT may be considered as an alternative treatment for severe CyN in patients who are refractory to G-CSF. It is postulated that in our patient the combined mutations (CyN and MEFV) may have contributed to the severity of this individual's symptoms. We suggest CyN patients who present with severe symptoms have evaluation with ELANE mutation testing, Periodic Fever Syndromes Panel, and routine marrow assessment with FISH, conventional cytogenetics, and morphological evaluation for MDS/AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2017/5375793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5286543PMC
January 2017

Alternative Donor Hematopoietic Cell Transplantation Conditioned With Myeloablative Busulfan, Fludarabine, and Melphalan is Well Tolerated and Effective Against High-risk Myeloid Malignancies.

J Pediatr Hematol Oncol 2016 11;38(8):e315-e318

Departments of *Pediatrics †Immunobiology ‡Medicine §Pathology ∥University of Arizona Cancer Center, University of Arizona ¶Banner University Medical Center, Tucson, AZ.

Busulfan, fludarabine, and melphalan as hematopoietic cell transplant conditioning, was used in 6 patients aged 1 to 19 years with very high-risk myeloid malignancies. This dose regimen had an acceptable toxicity profile resulting in complete donor engraftment even following transplantation of small 2/6 antigen disparate umbilical cord blood grafts. It provided excellent disease control as all patients had high-risk features in terms of cytogenetics, therapy-related leukemia, and/or significant measurable disease before transplant. All patients remain in remission, without acute or chronic graft-versus-host disease with a median follow-up of 24 months. A larger study is indicated to confirm the efficacy and safety of this regimen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPH.0000000000000621DOI Listing
November 2016

Targeted immunotherapy for pediatric solid tumors.

Oncoimmunology 2016 Mar 31;5(3):e1087637. Epub 2015 Aug 31.

Division of Hematology, Oncology, BMT, Department of Pediatrics, University of Arizona , Tucson, Ariz, USA.

Metastatic and refractory pediatric solid tumor malignancies continue to have a poor outcome despite the > 80% cure rates appreciated in many pediatric cancers. Targeted immunotherapy is impacting treatment and survival in these aggressive tumors. We review current promising immunotherapeutic approaches in the pediatric oncology solid tumor setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2015.1087637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839383PMC
March 2016

Post-transplant bendamustine reduces GvHD while preserving GvL in experimental haploidentical bone marrow transplantation.

Br J Haematol 2016 07 31;174(1):102-16. Epub 2016 Mar 31.

Department of Pediatrics, University of Arizona, Tucson, Arizona.

Advances in haploidentical bone marrow transplantation (h-BMT) have drastically broadened the treatment options for patients requiring BMT. The possibility of significantly reducing the complications resulting from graft-versus-host disease (GvHD) with the administration of post-transplant cyclophosphamide (PT-CY) has substantially improved the efficacy and applicability of T cell-replete h-BMT. However, higher frequency of disease recurrence remains a major challenge in h-BMT with PT-CY. There is a critical need to identify novel strategies to prevent GvHD while sparing the graft-versus-leukaemia (GvL) effect in h-BMT. To this end, we evaluated the impact of bendamustine (BEN), given post-transplant, on GvHD and GvL using clinically relevant murine h-BMT models. We provide results indicating that post-transplant bendamustine (PT-BEN) alleviates GvHD, significantly improving survival, while preserving engraftment and GvL effects. We further document that PT-BEN can mitigate GvHD even in the absence of Treg. Our results also indicate that PT-BEN is less myelosuppressive than PT-CY, significantly increasing the number and proportion of CD11b(+) Gr-1(hi) cells, while decreasing lymphoid cells. In vitro we observed that BEN enhances the suppressive function of myeloid-derived suppressor cells (MDSCs) while impairing the proliferation of T- and B-cells. These results advocate for the consideration of PT-BEN as a new therapeutic platform for clinical implementation in h-BMT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.14034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917459PMC
July 2016

Extramedullary Breast Relapse of Acute Lymphoblastic Leukemia Controlled with a Second Allogeneic/Autologous Hematopoietic Cell Transplant.

J Adolesc Young Adult Oncol 2015 Mar 3;4(1):50-3. Epub 2015 Mar 3.

2 Division of Hematology/Oncology/BMT, Department of Pediatrics, University of Arizona , Tucson, Arizona.

Relapse of acute lymphoblastic leukemia (ALL) in the breast is uncommon and often precedes systemic relapse, resulting in poor survival. We report the development of breast involvement of ALL in a 20-year-old woman 32 months after a related allogeneic peripheral blood hematopoietic cell transplantation (PBHCT) in first remission. This extramedullary relapse occurred in the continuous presence of complete donor chimerism. After systemic re-induction chemotherapy and a second PBHCT using donor cells that had been cryopreserved at first transplant, our patient has remained in second complete remission for more than 44 months.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/jayao.2014.0018DOI Listing
March 2015

Factors associated with improved outcomes after second allogeneic hematopoietic cell transplantation for relapsed pediatric leukemia.

Ann Hematol 2016 Mar 20;95(4):637-44. Epub 2016 Jan 20.

Department of Pediatrics, University of Arizona, PO Box 245073, 1501 N. Campbell Ave., Tucson, AZ, 85724-5073, USA.

A second allogeneic (allo) hematopoietic cell transplant (HCT) is an important therapeutic consideration for patients relapsing after their first. We conducted a retrospective review of 41 pediatric patients with leukemia that underwent a second allo-HCT at our institution. Overall, 53.7 and 43.9 % of patients were alive and disease-free at 1 and 5 years, respectively, after the second allo-HCT. The factors affecting outcome by both univariate and multivariate analysis were interval between transplants and the use of a myeloablative conditioning (MAC) regimen prior to second transplant. Outcomes were inferior in patients who received their second transplant <6 months from their first HCT when compared to patients in whom the interval between HCTs was 6-12 or more than 12 months. Interval between HCTs was also significant when each type of leukemia (acute lymphoblastic leukemia (ALL) n = 21, acute myelogenous leukemia (AML) n = 11, and chronic myelogenous leukemia (CML) n = 7) was analyzed separately. In univariate analysis, use of the same donor and use of a matched sibling donor resulted in significant improved outcome. There was not a significant association between disease-free survival (DFS) and age, remission status, use of total body irradiation (TBI) before second HCT, or type of leukemia. Second allogeneic HCT can be a curative therapeutic option for leukemia patients relapsing after their first transplant. As more targeted therapies have become available, patients that relapse after first HCT are more likely to achieve remission. Therefore, it is anticipated that there will be more candidates for second HCT with improved performance and remission status, ultimately leading to a better outcome with the second HCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-016-2599-9DOI Listing
March 2016

T Lymphocyte Inhibition by Tumor-Infiltrating Dendritic Cells Involves Ectonucleotidase CD39 but Not Arginase-1.

Biomed Res Int 2015 30;2015:891236. Epub 2015 Sep 30.

INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, 25020 Besançon, France.

T lymphocytes activated by dendritic cells (DC) which present tumor antigens play a key role in the antitumor immune response. However, in patients suffering from active cancer, DC are not efficient at initiating and supporting immune responses as they participate to T lymphocyte inhibition. DC in the tumor environment are functionally defective and exhibit a characteristic of immature phenotype, different to that of DC present in nonpathological conditions. The mechanistic bases underlying DC dysfunction in cancer responsible for the modulation of T-cell responses and tumor immune escape are still being investigated. Using two different mouse tumor models, we showed that tumor-infiltrating DC (TIDC) are constitutively immunosuppressive, exhibit a semimature phenotype, and impair responder T lymphocyte proliferation and activation by a mechanism involving CD39 ectoenzyme.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2015/891236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605267PMC
August 2016

Endoplasmic reticulum chaperones and their roles in the immunogenicity of cancer vaccines.

Front Oncol 2014 6;4:379. Epub 2015 Jan 6.

Department of Pediatrics, The University of Arizona , Tucson, AZ , USA.

The endoplasmic reticulum (ER) is a major site of passage for proteins en route to other organelles, to the cell surface, and to the extracellular space. It is also the transport route for peptides generated in the cytosol by the proteasome into the ER for loading onto major histocompatibility complex class I (MHC I) molecules for eventual antigen presentation at the cell surface. Chaperones within the ER are critical for many of these processes; however, outside the ER certain of those chaperones may play important and direct roles in immune responses. In some cases, particular ER chaperones have been utilized as vaccines against tumors or infectious disease pathogens when purified from tumor tissue or recombinantly generated and loaded with antigen. In other cases, the cell surface location of ER chaperones has implications for immune responses as well as possible tumor resistance. We have produced heat-shock protein/chaperone protein-based cancer vaccines called "chaperone-rich cell lysate" (CRCL) that are conglomerates of chaperones enriched from solid tumors by an isoelectric focusing technique. These preparations have been effective against numerous murine tumors, as well as in a canine with an advanced lung carcinoma treated with autologous CRCL. We also published extensive proteomic analyses of CRCL prepared from human surgically resected tumor samples. Of note, these preparations contained at least 10 ER chaperones and a number of other residents, along with many other chaperones/heat-shock proteins. Gene ontology and network analyses utilizing these proteins essentially recapitulate the antigen presentation pathways and interconnections. In conjunction with our current knowledge of cell surface/extracellular ER chaperones, these data collectively suggest that a systems-level view may provide insight into the potent immune stimulatory activities of CRCL with an emphasis on the roles of ER components in those processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2014.00379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4285071PMC
January 2015

Pediatric secondary chronic myeloid leukemia following cardiac transplantation for anthracycline-induced cardiomyopathy.

Pediatr Blood Cancer 2015 Jan 31;62(1):166-8. Epub 2014 Aug 31.

Department of Pediatrics, University of Arizona, Tucson, Arizona.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of the hematopoietic stem cell that is exceptionally rare in the first five years of life, particularly as a secondary malignancy. This report describes a case of secondary CML in a four-year-old female occurring after AML treatment. Interestingly, CML developed while on immunosuppression for a heart transplant due to anthracycline-induced cardiomyopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.25204DOI Listing
January 2015

Outcomes after hematopoietic stem cell transplantation for children with I-cell disease.

Biol Blood Marrow Transplant 2014 Nov 10;20(11):1847-51. Epub 2014 Jul 10.

Division of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minnesota.

Mucolipidosis type II (MLII), or I-cell disease, is a rare but severe disorder affecting localization of enzymes to the lysosome, generally resulting in death before the 10th birthday. Although hematopoietic stem cell transplantation (HSCT) has been used to successfully treat some lysosomal storage diseases, only 2 cases have been reported on the use of HSCT to treat MLII. For the first time, we describe the combined international experience in the use of HSCT for MLII in 22 patients. Although 95% of the patients engrafted, overall survival was low, with only 6 patients (27%) alive at last follow-up. The most common cause of death post-transplant was cardiovascular complications, most likely due to disease progression. Survivors were globally delayed in development and often required complex medical support, such as gastrostomy tubes for nutrition and tracheostomy with mechanical ventilation. Although HSCT has demonstrated efficacy in treating some lysosomal storage disorders, the neurologic outcome and survival for patents with MLII were poor. Therefore, new medical and cellular therapies should be sought for these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2014.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4194244PMC
November 2014

PIAS1 and STAT-3 impair the tumoricidal potential of IFN-γ-stimulated mouse dendritic cells generated with IL-15.

Eur J Immunol 2014 Aug 23;44(8):2489-2499. Epub 2014 May 23.

Department of Pediatrics, University of Arizona, Tucson, AZ, United States of America.

Primarily defined by their antigen-presenting property, dendritic cells (DCs) are being implemented as cancer vaccines in immunotherapeutic interventions. DCs can also function as direct tumor cell killers. How DC cytotoxic activity can be efficiently harnessed and the mechanisms controlling this nonconventional property are not fully understood. We report here that the tumoricidal potential of mouse DCs generated from myeloid precursors with GM-CSF and IL-15 (IL-15 DCs) can be triggered with the Toll-like receptor (TLR) 4 ligand lipopolysaccharide to a similar extent compared with that of their counterparts, conventionally generated with IL-4 (IL-4 DCs). The mechanism of tumor cell killing depends on the induction of iNOS expression by DCs. In contrast, interferon (IFN)-γ induces the cytotoxic activity of IL-4 but not IL-15 DCs. Although the IFN-γ-STAT-1 signaling pathway is overall functional in IL-15 DCs, IFN-γ fails to induce iNOS expression in these cells. iNOS expression is negatively controlled in IFN-γ-stimulated IL-15 DCs by the cooperation between the E3 SUMO ligase PIAS1 and STAT-3, and can be partially restored with PIAS1 siRNA and STAT-3 inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.201343803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4141036PMC
August 2014

Chemotherapeutic targeting of myeloid-derived suppressor cells.

Oncoimmunology 2014 Jan;3(1):e27359

Department of Pediatrics; Steele Children's Research Center; the University of Arizona Cancer Center; Tucson, AZ USA ; Cancer Biology Graduate Program; University of Arizona; Tucson, AZ USA ; Department of Immunobiology and BIO5 Institute; University of Arizona; Tucson, AZ USA.

Myeloid-derived suppressor cells (MDSCs), which expand in cancer-bearing hosts, contribute to the escape of malignant cells from immune destruction and impair the efficacy of immunotherapeutic interventions. We have recently demonstrated that the conventional chemotherapeutic agent doxorubicin selectively eliminates MDSCs, hence promoting the activity of immune effector cells and improving the therapeutic profile of adoptively transferred helper T lymphocytes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960296PMC
http://dx.doi.org/10.4161/onci.27359DOI Listing
January 2014