Publications by authors named "Robert Zeiser"

210 Publications

Demethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia.

Nat Commun 2021 11 8;12(1):6436. Epub 2021 Nov 8.

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Successful treatment of acute myeloid leukemia (AML) with chimeric antigen receptor (CAR) T cells is hampered by toxicity on normal hematopoietic progenitor cells and low CAR T cell persistence. Here, we develop third-generation anti-CD123 CAR T cells with a humanized CSL362-based ScFv and a CD28-OX40-CD3ζ intracellular signaling domain. This CAR demonstrates anti-AML activity without affecting the healthy hematopoietic system, or causing epithelial tissue damage in a xenograft model. CD123 expression on leukemia cells increases upon 5'-Azacitidine (AZA) treatment. AZA treatment of leukemia-bearing mice causes an increase in CTLA-4 anti-CD123 CAR T cell numbers following infusion. Functionally, the CTLA-4 anti-CD123 CAR T cells exhibit superior cytotoxicity against AML cells, accompanied by higher TNFα production and enhanced downstream phosphorylation of key T cell activation molecules. Our findings indicate that AZA increases the immunogenicity of AML cells, enhancing recognition and elimination of malignant cells by highly efficient CTLA-4 anti-CD123 CAR T cells.
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http://dx.doi.org/10.1038/s41467-021-26683-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8575966PMC
November 2021

Acute Graft--Host Disease, Infections, Vascular Events and Drug Toxicities Affecting the Central Nervous System.

Front Immunol 2021 6;12:748019. Epub 2021 Oct 6.

Department of Medicine I - Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for patients with hematological malignancies. Acute Graft host diseases (GVHD) is a major immune mediated side effect of allo-HCT that can affect the central nervous system (CNS) in addition to post-allo-HCT vascular events, drug toxicity or infections. Here we summarize and discuss recent preclinical data on the CNS as a target of acute GVHD and the known mechanisms contributing to neurotoxicity with a focus on microglia and T cells. We also discuss open questions in the field and place the findings made in mouse models in a clinical context. While in mice the neurological deficits can be assessed in a controlled fashion, in patients the etiology of the CNS damage is difficult to attribute to acute GVHD infections, vascular events, and drug-induced toxicity. Ultimately, we discuss novel therapies for GVHD of the CNS. Our understanding of the biological mechanisms that lead to neurotoxicity after allo-HCT increased over the last decade. This review provides insights into CNS manifestations of GVHD other etiologies of CNS damage in mice and patients.
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http://dx.doi.org/10.3389/fimmu.2021.748019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527894PMC
October 2021

Ruxolitinib for Chronic Graft-versus-Host Disease. Reply.

N Engl J Med 2021 10;385(17):1631-1632

Ospedale Pediatrico Bambino Gesù, Rome, Italy.

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http://dx.doi.org/10.1056/NEJMc2113499DOI Listing
October 2021

The impact of pulmonary function in patients undergoing autologous stem cell transplantation.

Blood Adv 2021 11;5(21):4327-4337

Department of Hematology/Oncology/Stem Cell Transplantation.

High-dose chemotherapy, followed by autologous hematopoietic stem cell transplantation (auto-HSCT), is an established therapy for patients with hematological malignancies. The age of patients undergoing auto-HSCT and, therefore, the comorbidities, has increased over the last decades. However, the assessment of organ dysfunction prior to auto-HSCT has not been well studied. Therefore, we retrospectively analyzed the association of clinical factors and lung and cardiac function with outcome and complications after conditioning with BEAM (BCNU/carmustine, etoposide, cytarabine, melphalan) or high-dose melphalan in patients undergoing auto-HSCT. This study included 629 patients treated at our institution between 2007 and 2017; 334 and 295 were conditioned with BEAM or high-dose melphalan, respectively. The median follow-up was 52 months (range, 0.2-152) and 50 months (range, 0.5-149), respectively. In the multivariate analysis, we identified that progressive disease, CO-diffusion capacity corrected for hemoglobin (DLCOcSB) ≤ 60% of predicted, Karnofsky Performance Status (KPS) ≤ 80%, Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score ≥ 4, and age > 70 years were associated with decreased overall survival (OS) in patients treated with BEAM. Similarly, DLCOcSB ≤ 60% of predicted, HCT-CI score ≥ 4, and age > 60 years were identified in patients treated with high-dose melphalan. Abnormalities in DLCOcSB ≤ 60% of predicted were associated with chemotherapy with lung-toxic substances, mediastinal radiotherapy, KPS ≤ 80%, current/previous smoking, and treatment in the intensive care unit. More often, patients with DLCOcSB ≤ 60% of predicted experienced nonrelapse mortality, including pulmonary causes of death. In summary, we identified DLCOcSB ≤ 60% of predicted as an independent risk factor for decreased OS in patients conditioned with BEAM or high-dose melphalan prior to auto-HSCT.
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http://dx.doi.org/10.1182/bloodadvances.2021004863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579263PMC
November 2021

Non-classical manifestations of acute GVHD.

Blood 2021 Sep 5. Epub 2021 Sep 5.

Hokkaido University Faculty of Medicine, Sapporo, Japan.

Acute graft-versus-host disease (GVHD) is a major life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). The classical target organs of acute GVHD include the intestines, liver, and skin. The damage of these organs is relatively easy to detect for the clinician as diarrhea, increased bilirubin, and rash. However, there is increasing evidence that also other organs, where the acute damage is less apparent or more difficult to distinguish from drug toxicity, such as the central nervous system, the lungs, the ovaries and testis, the thymus, the bone marrow and the kidney, can be target organs of acute GVHD. Here, we review current evidence for non-classical manifestations of acute GVHD in rodent models and in patients and discuss them in the context of novel emerging therapies for GVHD. A better understanding of the involvement of the non-classical GVHD target organs may help to improve patient outcomes after allo-HCT.
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http://dx.doi.org/10.1182/blood.2021012431DOI Listing
September 2021

Coevolving JAK2V617F+relapsed AML and donor T cells with PD-1 blockade after stem cell transplantation: an index case.

Blood Adv 2021 11;5(22):4701-4709

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

Relapse of myeloproliferative neoplasms (MPNs) after allogeneic hematopoietic stem cell transplantation (HSCT) is associated with poor outcomes, as therapeutic approaches to reinstate effective graft-versus-leukemia (GVL) responses remain suboptimal. Immune escape through overexpression of PD-L1 in JAK2V617F-mutated MPN provides a rationale for therapeutic PD-1 blockade, and indeed, clinical activity of nivolumab in relapsed MPN post-HSCT has been observed. Elucidation of the features of response following PD-1 blockade in such patients could inform novel therapeutic concepts that enhance GVL. Here, we report an integrated high-dimensional analysis using single-cell RNA sequencing, T-cell receptor sequencing, cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), and assay for transposase-accessible chromatin using sequencing (scATAC-seq), together with mass cytometry, in peripheral blood mononuclear cells collected at 6 timepoints before, during, and after transient response to PD-1 blockade from an index case of relapsed MPN following HSCT. Before nivolumab infusion, acute myeloid leukemia (AML) blasts demonstrated high expression of chemokines, and T cells were characterized by expression of interferon-response genes. This baseline inflammatory signature disappeared after nivolumab infusion. Clinical response was characterized by transient expansion of a polyclonal CD4+ T-cell population and contraction of an AML subpopulation that exhibited megakaryocytic features and elevated PD-L1 expression. At relapse, the proportion of the AML subpopulation with progenitor-like features progressively increased, suggesting coevolution of AML blasts and donor-derived T cells. We thus demonstrate how single-cell technologies can provide complementary insight into cellular mechanisms underlying response to PD-1 blockade, motivating future longitudinal high-dimensional single-cell studies of GVL responses in relapsed myeloid disease.
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http://dx.doi.org/10.1182/bloodadvances.2021004335DOI Listing
November 2021

Therapeutic targeting of endoplasmic reticulum stress in acute graft-versus-host disease.

Haematologica 2021 Aug 19. Epub 2021 Aug 19.

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner site Freiburg; and German Cancer Research Center (DKFZ), Heidelberg.

Acute graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), a potentially curative treatment for leukemia. Endoplasmic reticulum (ER) stress occurs when the protein folding capacity of the ER is oversaturated. How ER stress modulates tissue homeostasis in the context of alloimmunity is not well understood. We show that ER stress contributes to intestinal tissue injury during GVHD and can be targeted pharmacologically. We observed high levels of ER stress upon GVHD onset in a murine allo-HCT model and in human biopsies. These levels correlated with GVHD severity, underscoring a novel therapeutic potential. Elevated ER stress resulted in increased cell death of intestinal organoids. In a conditional knockout model, deletion of the ER stress regulator transcription factor Xbp1 in intestinal epithelial cells induced a general ER stress signaling disruption and aggravated GVHD lethality. This phenotype was mediated by changes in the production of anti-microbial peptides and the microbiome composition as well as activation of pro-apoptotic signaling. Inhibition of inositol-requiring enzyme 1 alpha (IRE1α), the most conserved signaling branch in ER stress, reduced GVHD development in mice. IRE1α blockade by the small molecule inhibitor 4µ8c improved intestinal cell viability, without impairing hematopoietic regeneration and T cell activity against tumor cells. Our findings in patient samples and mice indicate that excessive ER stress propagates tissue injury during GVHD. Reducing ER stress could improve the outcome of patients suffering from GVHD.
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http://dx.doi.org/10.3324/haematol.2021.278387DOI Listing
August 2021

Enhanced AC133-specific CAR T cell therapy induces durable remissions in mice with metastatic small cell lung cancer.

Cancer Lett 2021 Nov 15;520:385-399. Epub 2021 Aug 15.

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; BIOSS Center for Biological Signalling Studies, University of Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Germany.

Metastatic small cell lung cancer (SCLC) is not curable. While SCLC is initially sensitive to chemotherapy, remissions are short-lived. The relapse is induced by chemotherapy-selected tumor stem cells, which express the AC133 epitope of the CD133 stem cell marker. We studied the effectiveness of AC133-specific CAR T cells post-chemotherapy using human primary SCLC and an orthotopic xenograft mouse model. AC133-specific CAR T cells migrated to SCLC tumor lesions, reduced the tumor burden, and prolonged survival in a humanized orthotopic SCLC model, but were not able to entirely eliminate tumors. We identified CD73 and PD-L1 as immune-escape mechanisms and combined PD-1-inhibition and CD73-inhibition with CAR T cell treatment. This triple-immunotherapy induced cures in 25% of the mice, without signs of graft-versus-host disease or bone marrow failure. AC133 cancer stem cells and PD-L1CD73 myeloid cells were detectable in primary human SCLC tissues, suggesting that patients may benefit from the triple-immunotherapy. We conclude that the combination of AC133-specific CAR T cells, anti-PD-1-antibody and CD73-inhibitor specifically eliminates chemo-resistant tumor stem cells, overcomes SCLC-mediated T cell inhibition, and might induce long-term complete remission in an otherwise incurable disease.
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http://dx.doi.org/10.1016/j.canlet.2021.08.012DOI Listing
November 2021

IRE1 and PERK signaling regulates inflammatory responses in a murine model of contact hypersensitivity.

Allergy 2021 Jul 27. Epub 2021 Jul 27.

Allergy Research Group, Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background: Contact sensitizers may interfere with correct protein folding. Generation of un-/misfolded proteins can activate the IRE-1 or PERK signaling pathways initiating the unfolded protein response (UPR) and thereby determine inflammatory immune responses. We have analyzed the effect of sensitizers with different potencies on the induction of UPR activation/inhibition and the subsequent generation of a pro-inflammatory micromilieu in vitro as well as the effect of UPR modulation on the inflammatory response in the murine contact hypersensitivity (CHS) in vivo.

Methods: Semi-quantitative and quantitative PCR, fluorescence microscopy, ELISA, NF-κB activation and translocation assays, DC/keratinocyte co-culture assay, FACS, and in vivo CHS experiments were performed.

Results: Sensitizers and irritants activate IRE-1 and PERK in murine and human keratinocytes. Synergistic effects occur after combination of different weak sensitizers / addition of irritants. Moreover, tolerogenic dinitrothiocyanobenzene can be converted into a strong sensitizer by pre-activation of the UPR. Blocking UPR signaling results in decreased NF-κB activation and cytokine production in keratinocytes and in activation marker downregulation in a HaCaT/THP-1 co-culture. Interestingly, not only systemic but also topical application of UPR inhibitors abrogates CHS responses in vivo.

Conclusion: These observations highlight an important role of the UPR in determination of the inflammatory response in vitro and in vivo further underlining the importance of tissue stress and damage responses in the development of ACD and provide mechanistically based concepts as a basis for the development of new therapeutic approaches to treat allergic contact dermatitis.
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http://dx.doi.org/10.1111/all.15024DOI Listing
July 2021

β-microglobulin triggers NLRP3 inflammasome activation in tumor-associated macrophages to promote multiple myeloma progression.

Immunity 2021 08 20;54(8):1772-1787.e9. Epub 2021 Jul 20.

Department of Internal Medicine 5, University Hospital Erlangen, Erlangen, Germany. Electronic address:

As substantial constituents of the multiple myeloma (MM) microenvironment, pro-inflammatory macrophages have emerged as key promoters of disease progression, bone destruction, and immune impairment. We identify beta-2-microglobulin (β2m) as a driver in initiating inflammation in myeloma-associated macrophages (MAMs). Lysosomal accumulation of phagocytosed β2m promotes β2m amyloid aggregation in MAMs, resulting in lysosomal rupture and ultimately production of active interleukin-1β (IL-1β) and IL-18. This process depends on activation of the NLRP3 inflammasome after β2m accumulation, as macrophages from NLRP3-deficient mice lack efficient β2m-induced IL-1β production. Moreover, depletion or silencing of β2m in MM cells abrogates inflammasome activation in a murine MM model. Finally, we demonstrate that disruption of NLRP3 or IL-18 diminishes tumor growth and osteolytic bone destruction normally promoted by β2m-induced inflammasome signaling. Our results provide mechanistic evidence for β2m's role as an NLRP3 inflammasome activator during MM pathogenesis. Moreover, inhibition of NLRP3 represents a potential therapeutic approach in MM.
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http://dx.doi.org/10.1016/j.immuni.2021.07.002DOI Listing
August 2021

Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease.

N Engl J Med 2021 07;385(3):228-238

From the Department of Medicine I, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg (R.Z.), and Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, Dresden (J.M.M.) - both in Germany; the Unit of Blood Diseases and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, ASST Spedali Civili di Brescia, University of Brescia, Brescia (N.P.), UOC di Oncoematologia e TMO, Dipartimento Oncologico "la Maddalena," Palermo (M.M.), and Dipartimento di Oncoematologia Pediatrica, IRCCS, Ospedale Pediatrico Bambino Gesu', Sapienza, Università di Roma, Rome (F.L.) - all in Italy; the BMT Unit, Tel Aviv (Sourasky) Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (R.R.); the Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia (S.K.H.); the Department of Medicine, Sheikh Shakhbout Medical City, Mayo Clinic, Abu Dhabi, United Arab Emirates (S.K.H.); UCL Cancer Institute, Institute of Immunity and Transplantation, London (R.C.); the Department of Bone Marrow Transplantation and Onco-Hematology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland (S.G.); Acibadem University Hospital, Hematology Department, Istanbul, Turkey (A.U.); Incyte, Wilmington, DE (P.L.); Novartis Pharma, Basel, Switzerland (N.H., T.S.); Novartis Pharmaceuticals, East Hanover, NJ (M.G.); the Fred Hutchinson Cancer Research Center, Seattle (S.J.L.); and the Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan (T.T.).

Background: Chronic graft-versus-host disease (GVHD), a major complication of allogeneic stem-cell transplantation, becomes glucocorticoid-refractory or glucocorticoid-dependent in approximately 50% of patients. Robust data from phase 3 randomized studies evaluating second-line therapy for chronic GVHD are lacking. In retrospective surveys, ruxolitinib, a Janus kinase (JAK1-JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory or -dependent chronic GVHD.

Methods: This phase 3 open-label, randomized trial evaluated the efficacy and safety of ruxolitinib at a dose of 10 mg twice daily, as compared with the investigator's choice of therapy from a list of 10 commonly used options considered best available care (control), in patients 12 years of age or older with moderate or severe glucocorticoid-refractory or -dependent chronic GVHD. The primary end point was overall response (complete or partial response) at week 24; key secondary end points were failure-free survival and improved score on the modified Lee Symptom Scale at week 24.

Results: A total of 329 patients underwent randomization; 165 patients were assigned to receive ruxolitinib and 164 patients to receive control therapy. Overall response at week 24 was greater in the ruxolitinib group than in the control group (49.7% vs. 25.6%; odds ratio, 2.99; P<0.001). Ruxolitinib led to longer median failure-free survival than control (>18.6 months vs. 5.7 months; hazard ratio, 0.37; P<0.001) and higher symptom response (24.2% vs. 11.0%; odds ratio, 2.62; P = 0.001). The most common (occurring in ≥10% patients) adverse events of grade 3 or higher up to week 24 were thrombocytopenia (15.2% in the ruxolitinib group and 10.1% in the control group) and anemia (12.7% and 7.6%, respectively). The incidence of cytomegalovirus infections and reactivations was similar in the two groups.

Conclusions: Among patients with glucocorticoid-refractory or -dependent chronic GVHD, ruxolitinib led to significantly greater overall response, failure-free survival, and symptom response. The incidence of thrombocytopenia and anemia was greater with ruxolitinib. (Funded by Novartis and Incyte; REACH3 ClinicalTrials.gov number, NCT03112603.).
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http://dx.doi.org/10.1056/NEJMoa2033122DOI Listing
July 2021

Interfering With Inflammation: Heterogeneous Effects of Interferons in Graft--Host Disease of the Gastrointestinal Tract and Inflammatory Bowel Disease.

Front Immunol 2021 24;12:705342. Epub 2021 Jun 24.

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

The intestine can be the target of several immunologically mediated diseases, including graft-versus-host disease (GVHD) and inflammatory bowel disease (IBD). GVHD is a life-threatening complication that occurs after allogeneic hematopoietic stem cell transplantation. Involvement of the gastrointestinal tract is associated with a particularly high mortality. GVHD development starts with the recognition of allo-antigens in the recipient by the donor immune system, which elicits immune-mediated damage of otherwise healthy tissues. IBD describes a group of immunologically mediated chronic inflammatory diseases of the intestine. Several aspects, including genetic predisposition and immune dysregulation, are responsible for the development of IBD, with Crohn's disease and ulcerative colitis being the two most common variants. GVHD and IBD share multiple key features of their onset and development, including intestinal tissue damage and loss of intestinal barrier function. A further common feature in the pathophysiology of both diseases is the involvement of cytokines such as type I and II interferons (IFNs), amongst others. IFNs are a family of protein mediators produced as a part of the inflammatory response, typically to pathogens or malignant cells. Diverse, and partially paradoxical, effects have been described for IFNs in GVHD and IBD. This review summarizes current knowledge on the role of type I, II and III IFNs, including basic concepts and controversies about their functions in the context of GVHD and IBD. In addition, therapeutic options, research developments and remaining open questions are addressed.
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http://dx.doi.org/10.3389/fimmu.2021.705342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264264PMC
June 2021

Development of an integrated model of care for allogeneic stem cell transplantation facilitated by eHealth-the SMILe study.

Support Care Cancer 2021 Dec 5;29(12):8045-8057. Epub 2021 Jul 5.

Institute of Nursing Science, Department Public Health, University of Basel, Basel, Switzerland.

Purpose: Allogeneic stem cell transplantation would benefit from re-engineering care towards an integrated eHealth-facilitated care model. With this paper we aim to: (1) describe the development of an integrated care model (ICM) in allogeneic SteM-cell-transplantatIon faciLitated by eHealth (SMILe) by combining implementation, behavioral, and computer science methods (e.g., contextual analysis, Behavior Change Wheel, and user-centered design combined with agile software development); and (2) describe that model's characteristics and its application in clinical practice.

Methods: The SMILe intervention's development consisted of four steps, with implementation science methods informing each: (1) planning its set-up within a theoretical foundation; (2) using behavioral science methods to develop the content; (3) choosing and developing its delivery method (human/technology) using behavioral and computer science methods; and (4) describing its characteristics and application in clinical practice.

Results: The SMILe intervention is embedded within the eHealth enhanced Chronic Care Model, entailing four self-management intervention modules, targeting monitoring and follow-up of important medical and symptom-related parameters, infection prevention, medication adherence, and physical activity. Interventions are delivered partly face-to-face by a care coordinator embedded within the transplant team, and partly via the SMILeApp that connects patients to the transplant team, who can monitor and rapidly respond to any relevant changes within 1 year post-transplant.

Conclusion: This paper provides stepwise guidance on how implementation, behavioral, and computer science methods can be used to develop interventions aiming to improve care for stem cell transplant patients in real-world clinical settings. This new care model is currently being tested in a hybrid I effectiveness-implementation trial.
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http://dx.doi.org/10.1007/s00520-021-06328-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550349PMC
December 2021

Deciphering the role of Minor histocompatibility antigens for acute graft-versus-host disease.

Transplant Cell Ther 2021 07;27(7):523-524

Department of Medicine I - Medical centre - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; Comprehensive Cancer Center Freiburg (CCCF), Medical Center- University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; German Cancer Consortium (DKTK) Partner Site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany; Signalling Research Centres BIOSS and CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg. Electronic address:

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http://dx.doi.org/10.1016/j.jtct.2021.06.008DOI Listing
July 2021

Fever supports CD8 effector T cell responses by promoting mitochondrial translation.

Proc Natl Acad Sci U S A 2021 06 14;118(25). Epub 2021 Jun 14.

Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg im Breisgau, Germany;

Fever can provide a survival advantage during infection. Metabolic processes are sensitive to environmental conditions, but the effect of fever on T cell metabolism is not well characterized. We show that in activated CD8 T cells, exposure to febrile temperature (39 °C) augmented metabolic activity and T cell effector functions, despite having a limited effect on proliferation or activation marker expression. Transcriptional profiling revealed an up-regulation of mitochondrial pathways, which was consistent with increased mass and metabolism observed in T cells exposed to 39 °C. Through in vitro and in vivo models, we determined that mitochondrial translation is integral to the enhanced metabolic activity and function of CD8 T cells exposed to febrile temperature. Transiently exposing donor lymphocytes to 39 °C prior to infusion in a myeloid leukemia mouse model conferred enhanced therapeutic efficacy, raising the possibility that exposure of T cells to febrile temperatures could have clinical potential.
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http://dx.doi.org/10.1073/pnas.2023752118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237659PMC
June 2021

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: III. The 2020 Treatment of Chronic GVHD Report.

Transplant Cell Ther 2021 09 11;27(9):729-737. Epub 2021 Jun 11.

Clinical Division of Hematology, Medical University of Graz, Graz, Austria. Electronic address:

Positive results from recent clinical trials have significantly expanded current therapeutic options for patients with chronic graft-versus-host disease (GVHD). However, new insights into the associations between clinical characteristics of chronic GVHD, pathophysiologic mechanisms of disease, and the clinical and biological effects of novel therapeutic agents are required to allow for a more individualized approach to treatment. The current report is focused on setting research priorities and direction in the treatment of chronic GVHD. Detailed correlative scientific studies should be conducted in the context of clinical trials to evaluate associations between clinical outcomes and the biological effect of systemic therapeutics. For patients who require systemic therapy but not urgent initiation of glucocorticoids, clinical trials for initial systemic treatment of chronic GVHD should investigate novel agents as monotherapy without concurrently starting glucocorticoids, to avoid confounding biological, pathological, and clinical assessments. Clinical trials for treatment-refractory disease should specifically target patients with incomplete or suboptimal responses to most recent therapy who are early in their disease course. Close collaboration between academic medical centers, medical societies, and industry is needed to support an individualized, biology-based strategic approach to chronic GVHD therapy.
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http://dx.doi.org/10.1016/j.jtct.2021.05.004DOI Listing
September 2021

Insights from integrating clinical and preclinical studies advance understanding of graft-versus-host disease.

J Clin Invest 2021 06;131(12)

Masonic Cancer Center and Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, Minnesota, USA.

As a result of impressive increases in our knowledge of rodent and human immunology, the understanding of the pathophysiologic mechanisms underlying graft-versus-host disease (GVHD) has dramatically improved in the past 15 years. Despite improved knowledge, translation to clinical care has not proceeded rapidly, and results from experimental models have been inconsistent in their ability to predict the clinical utility of new therapeutic agents. In parallel, new tools in immunology have allowed in-depth analyses of the human system and have recently been applied in the field of clinical GVHD. Notwithstanding these advances, there is a relative paucity of mechanistic insights into human translational research, and this remains an area of high unmet need. Here we review selected recent advances in both preclinical experimental transplantation and translational human studies, including new insights into human immunology, the microbiome, and regenerative medicine. We focus on the fact that both approaches can interactively improve our understanding of both acute and chronic GVHD biology and open the door to improved therapeutics and successes.
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http://dx.doi.org/10.1172/JCI149296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203454PMC
June 2021

Immunomodulatory Therapies for the Treatment of Graft-versus-host Disease.

Hemasphere 2021 Jun 1;5(6):e581. Epub 2021 Jun 1.

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative therapy for patients suffering from hematological malignancies, and its therapeutic success is based on the graft-versus-leukemia (GvL) effect. Severe acute and chronic graft-versus-host disease (GvHD) are life-threatening complications after allo-HCT. To date, most of the approved treatment strategies for GvHD rely on broadly immunosuppressive regimens, which limit the beneficial GvL effect by reducing the cytotoxicity of anti-leukemia donor T-cells. Therefore, novel therapeutic strategies that rely on immunomodulatory rather than only immunosuppressive effects could help to improve patient outcomes. Treatments should suppress severe GvHD while preserving anti-leukemia immunity. New treatment strategies include the blockade of T-cell activation via inhibition of dipeptidyl peptidase 4 and cluster of differentiation 28-mediated co-stimulation, reduction of proinflammatory interleukin (IL)-2, IL-6 and tumor necrosis factor-α signaling, as well as kinase inhibition. Janus kinase (JAK)1/2 inhibition acts directly on T-cells, but also renders antigen presenting cells more tolerogenic and blocks dendritic cell-mediated T-cell activation and proliferation. Extracorporeal photopheresis, hypomethylating agent application, and low-dose IL-2 are powerful approaches to render the immune response more tolerogenic by regulatory T-cell induction. The transfer of immunomodulatory and immunosuppressive cell populations, including mesenchymal stromal cells and regulatory T-cells, showed promising results in GvHD treatment. Novel experimental procedures are based on metabolic reprogramming of donor T-cells by reducing glycolysis, which is crucial for cytotoxic T-cell proliferation and activity.
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http://dx.doi.org/10.1097/HS9.0000000000000581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171375PMC
June 2021

Oncogenic Activation in the Nonhematopoietic Bone Marrow Microenvironment Causes Myelodysplastic Syndrome in Mice.

Mol Cancer Res 2021 09 4;19(9):1596-1608. Epub 2021 Jun 4.

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

The bone marrow microenvironment (BMME) is key player in regulation and maintenance of hematopoiesis. Oncogenic mutations, causing constitutive activation of multiple tumor-promoting pathways, are frequently found in human cancer. So far in hematologic malignancies, mutations have only been reported to occur in hematopoietic cells. In this study, we investigated the effect of oncogenic expression in the BMME in a chimeric mouse model. We observed that an activating mutation of in the nonhematopoietic system leads to a phenotype resembling myelodysplastic syndrome (MDS) characterized by peripheral cytopenia, marked dysplasia within the myeloid lineage as well as impaired proliferation and differentiation capacity of hematopoietic stem and progenitor cells. The phenotypic changes could be reverted when the BM was re-isolated and transferred into healthy recipients, indicating that the -activation in the nonhematopoietic BMME was essential for the MDS phenotype. Gene expression analysis of sorted nonhematopoietic BM niche cells from mice revealed upregulation of multiple inflammation-related genes including IL1-superfamily members () and the NLPR3 inflammasome. Thus, pro-inflammatory IL1-signaling in the BMME may contribute to MDS development. Our findings show that a single genetic change in the nonhematopoietic BMME can cause an MDS phenotype. Oncogenic activation leads to pro-inflammatory signaling in the BMME which impairs HSPCs function. IMPLICATIONS: These findings may help to identify new therapeutic targets for MDS.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0275DOI Listing
September 2021

Donor lymphocyte infusions after first allogeneic hematopoietic stem-cell transplantation in adults with acute myeloid leukemia: a single-center landmark analysis.

Ann Hematol 2021 Sep 1;100(9):2339-2350. Epub 2021 Apr 1.

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is potentially curative for acute myeloid leukemia (AML). The inherent graft-versus-leukemia activity (GvL) may be optimized by donor lymphocyte infusions (DLI). Here we present our single-center experience of DLI use patterns and effectiveness, based on 342 consecutive adult patients receiving a first allo-HSCT for AML between 2009 and 2017. The median age at transplantation was 57 years (range 19-79), and the pre-transplant status was active disease in 58% and complete remission (CR) in 42% of cases. In a combined landmark analysis, patients in CR on day +30 and alive on day +100 were included. In this cohort (n=292), 93 patients received cryopreserved aliquots of peripheral blood-derived grafts for DLI (32%) and median survival was 55.7 months (2-year/5-year probability: 62%/49%). Median survival for patients receiving a first dose of DLI "preemptively," in the absence of relapse and guided by risk marker monitoring (preDLI; n=42), or only after hematological relapse (relDLI; n=51) was 40.9 months (2-year/5-year: 64%/43%) vs 10.4 months (2-year/5-year: 26%/10%), respectively. Survival was inferior when preDLI was initiated at a time of genetic risk marker detection vs mixed chimerism or clinical risk only. Time to first-dose preDLI vs time to first-dose relDLI was similar, suggesting that early warning and intrinsically lower dynamics of AML recurrence may contribute to effectiveness of preDLI-modified GvL activity. Future refinements of the preemptive DLI concept will benefit from collaborative efforts to diagnose measurable residual disease more reliably across the heterogeneous genomic spectrum of AML.
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http://dx.doi.org/10.1007/s00277-021-04494-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357755PMC
September 2021

A prospective single-center study on CNI-free GVHD prophylaxis with everolimus plus mycophenolate mofetil in allogeneic HCT.

Ann Hematol 2021 Aug 23;100(8):2095-2103. Epub 2021 Mar 23.

Department Hematology, Oncology & Stem Cell Transplantation, Faculty of Medicine and Medical Centre, University of Freiburg, Freiburg, Germany.

We report a single-center phase I/II trial exploring the combination of everolimus (EVE) and mycophenolate mofetil (MMF) as calcineurin inhibitor (CNI)-free GVHD prophylaxis for 24 patients with hematologic malignancies and indication for allogeneic HCT after a high dose or reduced-intensity ablative conditioning. The study was registered as EudraCT-2007-001892-12 and Clinicaltrials.gov as NCT00856505. All patients received PBSC grafts and no graft failure occurred. 7/24 patients (29%) developed acute grades III and IV GVHD (aGVHD), 16/19 evaluable patients (84%) developed chronic GVHD (cGVHD) of all grades, and 6/19 (31.6%) of higher grades. No severe toxicities related to study medication were observed. The median follow-up of all surviving patients is 2177 days. The 3-year OS was 45.2% (95% CI: 27.4-61.4%), and the 3-year PFS was 38.7% (95% CI: 22.0-55.1%). The cumulative incidence of relapse at 1 year and 3 year was 25% (95% CI: 12.5-50.0%), and 33.3% (95% CI: 18.9-58.7%), the cumulative incidence of NRM at 1 year and 3 years was 20.8% (95%CI: 9.6-45.5%), and 29.2% (95%CI: 15.6-54.4%), respectively. The utilization of CNI-free GVHD prophylaxis with EVE+MMF resulted in high rates of acute and chronic GVHD. Therefore, we do not recommend a CNI-free combination of mTOR inhibitor EVE with MMF as the sole GVHD prophylaxis. In subsequent studies, this combination should be modified, e.g., with further components like post-transplant cyclophosphamide (PTCy) or anti-thymocyte globulin (ATG).
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http://dx.doi.org/10.1007/s00277-021-04487-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285343PMC
August 2021

The Role of Immune Checkpoint Molecules for Relapse After Allogeneic Hematopoietic Cell Transplantation.

Front Immunol 2021 5;12:634435. Epub 2021 Mar 5.

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, Albert Ludwigs University (ALU), Freiburg, Germany.

Immune checkpoint molecules represent physiological brakes of the immune system that are essential for the maintenance of immune homeostasis and prevention of autoimmunity. By inhibiting these negative regulators of the immune response, immune checkpoint blockade can increase anti-tumor immunity, but has been primarily successful in solid cancer therapy and Hodgkin lymphoma so far. Allogeneic hematopoietic cell transplantation (allo-HCT) is a well-established cellular immunotherapy option with the potential to cure hematological cancers, but relapse remains a major obstacle. Relapse after allo-HCT is mainly thought to be attributable to loss of the graft-versus-leukemia (GVL) effect and hence escape of tumor cells from the allogeneic immune response. One potential mechanism of immune escape from the GVL effect is the inhibition of allogeneic T cells via engagement of inhibitory receptors on their surface including PD-1, CTLA-4, TIM3, and others. This review provides an overview of current evidence for a role of immune checkpoint molecules for relapse and its treatment after allo-HCT, as well as discussion of the immune mediated side effect graft-vs.-host disease. We discuss the expression of different immune checkpoint molecules on leukemia cells and T cells in patients undergoing allo-HCT. Furthermore, we review mechanistic insights gained from preclinical studies and summarize clinical trials assessing immune checkpoint blockade for relapse after allo-HCT.
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http://dx.doi.org/10.3389/fimmu.2021.634435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973115PMC
September 2021

Graft-versus-host disease prophylaxis: Pathophysiology-based review on current approaches and future directions.

Blood Rev 2021 07 26;48:100792. Epub 2020 Dec 26.

Department of Hematology, University Hospital Virgen del Rocio, Instituto de Biomedicina de Sevilla (IBIS/CSIC/CIBERONC), Universidad de Sevilla, Spain. Electronic address:

Graft-versus-host disease (GvHD) was first described in 1959, since then major efforts have been made in order to understand its physiopathology and animal models have played a key role. Three steps, involving different pathways, have been recognised in either acute and chronic GvHD, identifying them as two distinct entities. In order to reduce GvHD incidence and severity, prophylactic measures were added to transplant protocols. The combination of a calcineurin inhibitor (CNI) plus an antimetabolite remains the standard of care. Better knowledge of GvHD pathophysiology has moved this field forward and nowadays different drugs are being used on a daily basis. Improving GvHD prophylaxis is a major goal as it would translate into less non-relapse mortality and better overall survival. As compared to CNI plus methotrexate the combination of CNI plus mycophenolate mophetil (MMF) allows us to obtain similar results in terms of GvHD incidence but a lower toxicity rate in terms of neutropenia or mucositis. The use of ATG has been related to a lower risk of acute and chronic GvHD in prospective randomized trials as well as the use of posttransplant Cyclophosphamide, with no or marginal impact on overall survival but with an improvement in GvHD-relapse free survival (GRFS). The use of sirolimus has been related to a lower risk of acute GvHD and significantly influenced overall survival in one prospective randomized trial. Other prospective trials have evaluated the use of receptors such as CCR5 or α4β7 to avoid T-cells trafficking into GvHD target organs, cytokine blockers or immune check point agonists. Also, epigenetic modifiers have shown promising results in phase II trials. Attention should be paid to graft-versus-leukemia, infections and immune recovery before bringing new prophylactic strategies to clinical practice. Although the list of novel agents for GvHD prophylaxis is growing, randomized trials are still lacking for many of them.
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http://dx.doi.org/10.1016/j.blre.2020.100792DOI Listing
July 2021

Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms.

Nature 2020 12 25;588(7836):157-163. Epub 2020 Nov 25.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Janus kinases (JAKs) mediate responses to cytokines, hormones and growth factors in haematopoietic cells. The JAK gene JAK2 is frequently mutated in the ageing haematopoietic system and in haematopoietic cancers. JAK2 mutations constitutively activate downstream signalling and are drivers of myeloproliferative neoplasm (MPN). In clinical use, JAK inhibitors have mixed effects on the overall disease burden of JAK2-mutated clones, prompting us to investigate the mechanism underlying disease persistence. Here, by in-depth phosphoproteome profiling, we identify proteins involved in mRNA processing as targets of mutant JAK2. We found that inactivation of YBX1, a post-translationally modified target of JAK2, sensitizes cells that persist despite treatment with JAK inhibitors to apoptosis and results in RNA mis-splicing, enrichment for retained introns and disruption of the transcriptional control of extracellular signal-regulated kinase (ERK) signalling. In combination with pharmacological JAK inhibition, YBX1 inactivation induces apoptosis in JAK2-dependent mouse and primary human cells, causing regression of the malignant clones in vivo, and inducing molecular remission. This identifies and validates a cell-intrinsic mechanism whereby differential protein phosphorylation causes splicing-dependent alterations of JAK2-ERK signalling and the maintenance of JAK2 malignant clones. Therapeutic targeting of YBX1-dependent ERK signalling in combination with JAK2 inhibition could thus eradicate cells harbouring mutations in JAK2.
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http://dx.doi.org/10.1038/s41586-020-2968-3DOI Listing
December 2020

Ruxolitinib-ECP combination treatment for refractory severe chronic graft-versus-host disease.

Bone Marrow Transplant 2021 04 17;56(4):909-916. Epub 2020 Nov 17.

Department of Medicine I, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany.

Glucocorticoid-refractory (SR) chronic (c) graft-versus-host disease (GVHD) is a multisystem immunological disease and the leading cause of non-relapse mortality (NRM) in patients surviving longer than 2 years after allogeneic hematopoietic cell transplantation. Both ruxolitinib (RUX) and extracorporeal photopheresis (ECP) have shown activity for SR-cGVHD which motivated us to treat refractory cGHVD patients with the RUX-ECP combination. In this retrospective survey, 23 patients received RUX-ECP as salvage therapy for SR-cGVHD. The best response (CR or PR) at any time point during treatment was 74% (17/23) including 9% (2/23) CR and 65% (15/23) PR. The 24-months-survival was 75% (CI 56.0-94.1). Newly diagnosed cytopenia occurred in 22% (5/23) and CMV reactivation was observed in 26% (6/23) of the patients. Serum levels of soluble interleukin-2 receptor (sIL-2R) correlated with response. Our retrospective analysis shows that the RUX-ECP combination is safe and has activity in a fraction of patients with SR-cGVHD, which needs validation in a prospective trial.
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http://dx.doi.org/10.1038/s41409-020-01122-8DOI Listing
April 2021

New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions.

Front Immunol 2020 9;11:578314. Epub 2020 Oct 9.

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Chronic graft-versus-host disease (cGvHD) is a severe complication of allogeneic hematopoietic stem cell transplantation that affects various organs leading to a reduced quality of life. The condition often requires enduring immunosuppressive therapy, which can also lead to the development of severe side effects. Several approaches including small molecule inhibitors, antibodies, cytokines, and cellular therapies are now being developed for the treatment of cGvHD, and some of these therapies have been or are currently tested in clinical trials. In this review, we discuss these emerging therapies with particular emphasis on tyrosine kinase inhibitors (TKIs). TKIs are a class of compounds that inhibits tyrosine kinases, thereby preventing the dissemination of growth signals and activation of key cellular proteins that are involved in cell growth and division. Because they have been shown to inhibit key kinases in both B cells and T cells that are involved in the pathophysiology of cGvHD, TKIs present new promising therapeutic approaches. Ibrutinib, a Bruton tyrosine kinase (Btk) inhibitor, has recently been approved by the Food and Drug Administration (FDA) in the United States for the treatment of adult patients with cGvHD after failure of first-line of systemic therapy. Also, Janus Associated Kinases (JAK1 and JAK2) inhibitors, such as itacitinib (JAK1) and ruxolitinib (JAK1 and 2), are promising in the treatment of cGvHD. Herein, we present the current status and future directions of the use of these new drugs with particular spotlight on their targeting of specific intracellular signal transduction cascades important for cGvHD, in order to shed some light on their possible mode of actions.
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http://dx.doi.org/10.3389/fimmu.2020.578314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583636PMC
June 2021

Immune modulatory effects of oncogenic KRAS in cancer.

Nat Commun 2020 10 28;11(1):5439. Epub 2020 Oct 28.

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Oncogenic KRAS mutations are the most frequent mutations in human cancer, but most difficult to target. While sustained proliferation caused by oncogenic KRAS-downstream signalling is a main driver of carcinogenesis, there is increasing evidence that it also mediates autocrine effects and crosstalk with the tumour microenvironment (TME). Here, we discuss recent reports connecting KRAS mutations with tumour-promoting inflammation and immune modulation caused by KRAS that leads to immune escape in the TME. We discuss the preclinical work on KRAS-induced inflammation and immune modulation in the context of currently ongoing clinical trials targeting cancer entities that carry KRAS mutations and strategies to overcome the oncogene-induced effects on the immune system.
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http://dx.doi.org/10.1038/s41467-020-19288-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595113PMC
October 2020

Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans.

Sci Transl Med 2020 10;12(567)

Department of Internal Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany.

Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic cell transplantation (allo-HCT) has a dismal prognosis. We found that T cells of patients relapsing with AML after allo-HCT exhibited reduced glycolysis and interferon-γ production. Functional studies in multiple mouse models of leukemia showed that leukemia-derived lactic acid (LA) interfered with T cell glycolysis and proliferation. Mechanistically, LA reduced intracellular pH in T cells, led to lower transcription of glycolysis-related enzymes, and decreased activity of essential metabolic pathways. Metabolic reprogramming by sodium bicarbonate (NaBi) reversed the LA-induced low intracellular pH, restored metabolite concentrations, led to incorporation of LA into the tricarboxylic acid cycle as an additional energy source, and enhanced graft-versus-leukemia activity of murine and human T cells. NaBi treatment of post-allo-HCT patients with relapsed AML improved metabolic fitness and interferon-γ production in T cells. Overall, we show that metabolic reprogramming of donor T cells is a pharmacological strategy for patients with relapsed AML after allo-HCT.
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http://dx.doi.org/10.1126/scitranslmed.abb8969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8529950PMC
October 2020
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