Publications by authors named "Ronjon Chakraverty"

65 Publications

Graft Versus Leukemia: Current Status and Future Perspectives.

J Clin Oncol 2021 Feb 12;39(5):361-372. Epub 2021 Jan 12.

MRC Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom.

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http://dx.doi.org/10.1200/JCO.20.01801DOI Listing
February 2021

Predictors of recovery following allogeneic CD34+-selected cell infusion without conditioning to correct poor graft function.

Haematologica 2020 11 1;105(11):2639-2646. Epub 2020 Nov 1.

Department of Hematology, University College Hospital NHS Trust; Cancer Institute UCL, London.

Poor graft function is a serious complication following allogeneic hematopoietic stem cell transplantation. Infusion of CD34+-selected stem cells without pre-conditioning has been used to correct poor graft function, but predictors of recovery are unclear. We report the outcome of 62 consecutive patients who had primary or secondary poor graft function who underwent a CD34+-selected stem cell infusion from the same donor without further conditioning. Forty-seven of 62 patients showed hematological improvement and became permanently transfusion and growth factor-independent. In multivariate analysis, parameters significantly associated with recovery were shared CMV seronegative status for recipient/donor, the absence of active infection and matched recipient/donor sex. Recovery was similar in patients with mixed and full donor chimerism. Five -year overall survival was 74.4% (95% CI 59-89) in patients demonstrating complete recovery, 16.7% (95% CI 3-46) in patients with partial recovery and 22.2% (CI 95% 5-47) in patients with no response. In patients with count recovery, those with poor graft function in 1-2 lineages had superior 5-year overall survival (93.8%, 95% CI 82-99) than those with tri-lineage failure (53%, 95% CI 34-88). New strategies including cytokine or agonist support, or second transplant need to be investigated in patients who do not recover.
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http://dx.doi.org/10.3324/haematol.2019.226340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604618PMC
November 2020

Idelalisib treatment prior to allogeneic stem cell transplantation for patients with chronic lymphocytic leukemia: a report from the EBMT chronic malignancies working party.

Bone Marrow Transplant 2020 Oct 2. Epub 2020 Oct 2.

University of Heidelberg, Heidelberg, Germany.

No studies have been reported so far on bridging treatment with idelalisib for patients with chronic lymphocytic leukemia (CLL) prior to allogeneic hematopoietic cell transplantation (alloHCT). To study potential carry-over effects of idelalisib and to assess the impact of pathway-inhibitor (PI) failure we performed a retrospective EBMT registry-based study. Patients with CLL who had a history of idelalisib treatment and received a first alloHCT between 2015 and 2017 were eligible. Data on 72 patients (median age 58 years) were analyzed. Forty percent of patients had TP53 CLL and 64% had failed on at least one PI. No primary graft failure occurred. Cumulative incidences of acute GVHD °II-IV and chronic GVHD were 51% and 39%, respectively. Estimates for 2-year overall survival (OS), progression-free survival (PFS), and cumulative incidences of relapse/progression (CIR) and non-relapse mortality NRM were 59%, 44%, 25%, and 31%. In univariate analysis, drug sensitivity was a strong risk factor. For patients who had failed neither PI treatment nor chemoimmunotherapy (CIT) the corresponding 2-year estimates were 73%, 65%, 15%, and 20%, respectively. In conclusion, idelalisib may be considered as an option for bridging therapy prior to alloHCT. Owing to the high risk for acute GVHD intensified clinical monitoring is warranted.
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http://dx.doi.org/10.1038/s41409-020-01069-wDOI Listing
October 2020

Graft-versus-host disease reduces lymph node display of tissue-restricted self-antigens and promotes autoimmunity.

J Clin Invest 2020 04;130(4):1896-1911

UCL Cancer Institute, and.

Acute graft-versus-host disease (GVHD) is initially triggered by alloreactive T cells, which damage peripheral tissues and lymphoid organs. Subsequent transition to chronic GVHD involves the emergence of autoimmunity, although the underlying mechanisms driving this process are unclear. Here, we tested the hypothesis that acute GVHD blocks peripheral tolerance of autoreactive T cells by impairing lymph node (LN) display of peripheral tissue-restricted antigens (PTAs). At the initiation of GVHD, LN fibroblastic reticular cells (FRCs) rapidly reduced expression of genes regulated by DEAF1, an autoimmune regulator-like transcription factor required for intranodal expression of PTAs. Subsequently, GVHD led to the selective elimination of the FRC population, and blocked the repair pathways required for its regeneration. We used a transgenic mouse model to show that the loss of presentation of an intestinal PTA by FRCs during GVHD resulted in the activation of autoaggressive T cells and gut injury. Finally, we show that FRCs normally expressed a unique PTA gene signature that was highly enriched for genes expressed in the target organs affected by chronic GVHD. In conclusion, acute GVHD damages and prevents repair of the FRC network, thus disabling an essential platform for purging autoreactive T cells from the repertoire.
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http://dx.doi.org/10.1172/JCI133102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108931PMC
April 2020

The Obese Liver Environment Mediates Conversion of NK Cells to a Less Cytotoxic ILC1-Like Phenotype.

Front Immunol 2019 11;10:2180. Epub 2019 Sep 11.

Department of Surgery and Cancer, Imperial College London, London, United Kingdom.

The liver contains both NK cells and their less cytotoxic relatives, ILC1. Here, we investigate the role of NK cells and ILC1 in the obesity-associated condition, non-alcoholic fatty liver disease (NAFLD). In the livers of mice suffering from NAFLD, NK cells are less able to degranulate, express lower levels of perforin and are less able to kill cancerous target cells than those from healthy animals. This is associated with a decreased ability to kill cancer cells . On the other hand, we find that perforin-deficient mice suffer from less severe NAFLD, suggesting that this reduction in NK cell cytotoxicity may be protective in the obese liver, albeit at the cost of increased susceptibility to cancer. The decrease in cytotoxicity is associated with a shift toward a transcriptional profile characteristic of ILC1, increased expression of the ILC1-associated proteins CD200R1 and CD49a, and an altered metabolic profile mimicking that of ILC1. We show that the conversion of NK cells to this less cytotoxic phenotype is at least partially mediated by TGFβ, which is expressed at high levels in the obese liver. Finally, we show that reduced cytotoxicity is also a feature of NK cells in the livers of human NAFLD patients.
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http://dx.doi.org/10.3389/fimmu.2019.02180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749082PMC
October 2020

A wave of monocytes is recruited to replenish the long-term Langerhans cell network after immune injury.

Sci Immunol 2019 08;4(38)

Institute for Immunity and Transplantation, Division of Infection and Immunity, University College London, London NW3 2PF, UK and Cancer Institute Department of Haematology, Division of Cancer Studies, University College London, London WC1E 6DD, UK.

A dense population of embryo-derived Langerhans cells (eLCs) is maintained within the sealed epidermis without contribution from circulating cells. When this network is perturbed by transient exposure to ultraviolet light, short-term LCs are temporarily reconstituted from an initial wave of monocytes but thought to be superseded by more permanent repopulation with undefined LC precursors. However, the extent to which this process is relevant to immunopathological processes that damage LC population integrity is not known. Using a model of allogeneic hematopoietic stem cell transplantation, where alloreactive T cells directly target eLCs, we have asked whether and how the original LC network is ultimately restored. We find that donor monocytes, but not dendritic cells, are the precursors of long-term LCs in this context. Destruction of eLCs leads to recruitment of a wave of monocytes that engraft in the epidermis and undergo a sequential pathway of differentiation via transcriptionally distinct EpCAM precursors. Monocyte-derived LCs acquire the capacity of self-renewal, and proliferation in the epidermis matched that of steady-state eLCs. However, we identified a bottleneck in the differentiation and survival of epidermal monocytes, which, together with the slow rate of renewal of mature LCs, limits repair of the network. Furthermore, replenishment of the LC network leads to constitutive entry of cells into the epidermal compartment. Thus, immune injury triggers functional adaptation of mechanisms used to maintain tissue-resident macrophages at other sites, but this process is highly inefficient in the skin.
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http://dx.doi.org/10.1126/sciimmunol.aax8704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894529PMC
August 2019

Unraveling the Mechanisms of Cutaneous Graft-Versus-Host Disease.

Front Immunol 2018 2;9:963. Epub 2018 May 2.

UCL Cancer Institute, University College London, London, United Kingdom.

The skin is the most common target organ affected by graft-versus-host disease (GVHD), with severity and response to therapy representing important predictors of patient survival. Although many of the initiating events in GVHD pathogenesis have been defined, less is known about why treatment resistance occurs or why there is often a permanent failure to restore tissue homeostasis. Emerging data suggest that the unique immune microenvironment in the skin is responsible for defining location- and context-specific mechanisms of injury that are distinct from those involved in other target organs. In this review, we address recent advances in our understanding of GVHD biology in the skin and outline the new research themes that will ultimately enable design of precision therapies.
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http://dx.doi.org/10.3389/fimmu.2018.00963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940745PMC
July 2019

Erratum: Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.

Authors:
Nimitha R Mathew Francis Baumgartner Lukas Braun David O'Sullivan Simone Thomas Miguel Waterhouse Tony A Müller Kathrin Hanke Sanaz Taromi Petya Apostolova Anna L Illert Wolfgang Melchinger Sandra Duquesne Annette Schmitt-Graeff Lena Osswald Kai-Li Yan Arnim Weber Sonia Tugues Sabine Spath Dietmar Pfeifer Marie Follo Rainer Claus Michael Lübbert Christoph Rummelt Hartmut Bertz Ralph Wäsch Johanna Haag Andrea Schmidts Michael Schultheiss Dominik Bettinger Robert Thimme Evelyn Ullrich Yakup Tanriver Giang Lam Vuong Renate Arnold Philipp Hemmati Dominik Wolf Markus Ditschkowski Cordula Jilg Konrad Wilhelm Christian Leiber Sabine Gerull Jörg Halter Claudia Lengerke Thomas Pabst Thomas Schroeder Guido Kobbe Wolf Rösler Soroush Doostkam Stephan Meckel Kathleen Stabla Stephan K Metzelder Sebastian Halbach Tilman Brummer Zehan Hu Joern Dengjel Björn Hackanson Christoph Schmid Udo Holtick Christof Scheid Alexandros Spyridonidis Friedrich Stölzel Rainer Ordemann Lutz P Müller Flore Sicre-de-Fontbrune Gabriele Ihorst Jürgen Kuball Jan E Ehlert Daniel Feger Eva-Maria Wagner Jean-Yves Cahn Jacqueline Schnell Florian Kuchenbauer Donald Bunjes Ronjon Chakraverty Simon Richardson Saar Gill Nicolaus Kröger Francis Ayuk Luca Vago Fabio Ciceri Antonia M Müller Takeshi Kondo Takanori Teshima Susan Klaeger Bernhard Kuster Dennis Dong Hwan Kim Daniel Weisdorf Walter van der Velden Daniela Dörfel Wolfgang Bethge Inken Hilgendorf Andreas Hochhaus Geoffroy Andrieux Melanie Börries Hauke Busch John Magenau Pavan Reddy Myriam Labopin Joseph H Antin Andrea S Henden Geoffrey R Hill Glen A Kennedy Merav Bar Anita Sarma Donal McLornan Ghulam Mufti Betul Oran Katayoun Rezvani Omid Shah Robert S Negrin Arnon Nagler Marco Prinz Andreas Burchert Andreas Neubauer Dietrich Beelen Andreas Mackensen Nikolas von Bubnoff Wolfgang Herr Burkhard Becher Gerard Socié Michael A Caligiuri Eliana Ruggiero Chiara Bonini Georg Häcker Justus Duyster Jürgen Finke Erika Pearce Bruce R Blazar Robert Zeiser

Nat Med 2018 Apr;24(4):526

This corrects the article DOI: 10.1038/nm.4484.
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http://dx.doi.org/10.1038/nm0418-526cDOI Listing
April 2018

Peripheral tissues reprogram CD8+ T cells for pathogenicity during graft-versus-host disease.

JCI Insight 2018 03 8;3(5). Epub 2018 Mar 8.

Haematology, UCL Cancer Institute and Institute of Immunity & Transplantation, London, United Kingdom (UK).

Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic stem cell transplantation induced by the influx of donor-derived effector T cells (TE) into peripheral tissues. Current treatment strategies rely on targeting systemic T cells; however, the precise location and nature of instructions that program TE to become pathogenic and trigger injury are unknown. We therefore used weighted gene coexpression network analysis to construct an unbiased spatial map of TE differentiation during the evolution of GVHD and identified wide variation in effector programs in mice and humans according to location. Idiosyncrasy of effector programming in affected organs did not result from variation in T cell receptor repertoire or the selection of optimally activated TE. Instead, TE were reprogrammed by tissue-autonomous mechanisms in target organs for site-specific proinflammatory functions that were highly divergent from those primed in lymph nodes. In the skin, we combined the correlation-based network with a module-based differential expression analysis and showed that Langerhans cells provided in situ instructions for a Notch-dependent T cell gene cluster critical for triggering local injury. Thus, the principal determinant of TE pathogenicity in GVHD is the final destination, highlighting the need for target organ-specific approaches to block immunopathology while avoiding global immune suppression.
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http://dx.doi.org/10.1172/jci.insight.97011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922296PMC
March 2018

Redirection to the bone marrow improves T cell persistence and antitumor functions.

J Clin Invest 2018 05 9;128(5):2010-2024. Epub 2018 Apr 9.

University College London (UCL) Cancer Institute, London, United Kingdom.

A key predictor for the success of gene-modified T cell therapies for cancer is the persistence of transferred cells in the patient. The propensity of less differentiated memory T cells to expand and survive efficiently has therefore made them attractive candidates for clinical application. We hypothesized that redirecting T cells to specialized niches in the BM that support memory differentiation would confer increased therapeutic efficacy. We show that overexpression of chemokine receptor CXCR4 in CD8+ T cells (TCXCR4) enhanced their migration toward vascular-associated CXCL12+ cells in the BM and increased their local engraftment. Increased access of TCXCR4 to the BM microenvironment induced IL-15-dependent homeostatic expansion and promoted the differentiation of memory precursor-like cells with low expression of programmed death-1, resistance to apoptosis, and a heightened capacity to generate polyfunctional cytokine-producing effector cells. Following transfer to lymphoma-bearing mice, TCXCR4 showed a greater capacity for effector expansion and better tumor protection, the latter being independent of changes in trafficking to the tumor bed or local out-competition of regulatory T cells. Thus, redirected homing of T cells to the BM confers increased memory differentiation and antitumor immunity, suggesting an innovative solution to increase the persistence and functions of therapeutic T cells.
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http://dx.doi.org/10.1172/JCI97454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919805PMC
May 2018

Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.

Authors:
Nimitha R Mathew Francis Baumgartner Lukas Braun David O'Sullivan Simone Thomas Miguel Waterhouse Tony A Müller Kathrin Hanke Sanaz Taromi Petya Apostolova Anna L Illert Wolfgang Melchinger Sandra Duquesne Annette Schmitt-Graeff Lena Osswald Kai-Li Yan Arnim Weber Sonia Tugues Sabine Spath Dietmar Pfeifer Marie Follo Rainer Claus Michael Lübbert Christoph Rummelt Hartmut Bertz Ralph Wäsch Johanna Haag Andrea Schmidts Michael Schultheiss Dominik Bettinger Robert Thimme Evelyn Ullrich Yakup Tanriver Giang Lam Vuong Renate Arnold Philipp Hemmati Dominik Wolf Markus Ditschkowski Cordula Jilg Konrad Wilhelm Christian Leiber Sabine Gerull Jörg Halter Claudia Lengerke Thomas Pabst Thomas Schroeder Guido Kobbe Wolf Rösler Soroush Doostkam Stephan Meckel Kathleen Stabla Stephan K Metzelder Sebastian Halbach Tilman Brummer Zehan Hu Joern Dengjel Björn Hackanson Christoph Schmid Udo Holtick Christof Scheid Alexandros Spyridonidis Friedrich Stölzel Rainer Ordemann Lutz P Müller Flore Sicre-de-Fontbrune Gabriele Ihorst Jürgen Kuball Jan E Ehlert Daniel Feger Eva-Maria Wagner Jean-Yves Cahn Jacqueline Schnell Florian Kuchenbauer Donald Bunjes Ronjon Chakraverty Simon Richardson Saar Gill Nicolaus Kröger Francis Ayuk Luca Vago Fabio Ciceri Antonia M Müller Takeshi Kondo Takanori Teshima Susan Klaeger Bernhard Kuster Dennis Dong Hwan Kim Daniel Weisdorf Walter van der Velden Daniela Dörfel Wolfgang Bethge Inken Hilgendorf Andreas Hochhaus Geoffroy Andrieux Melanie Börries Hauke Busch John Magenau Pavan Reddy Myriam Labopin Joseph H Antin Andrea S Henden Geoffrey R Hill Glen A Kennedy Merav Bar Anita Sarma Donal McLornan Ghulam Mufti Betul Oran Katayoun Rezvani Omid Shah Robert S Negrin Arnon Nagler Marco Prinz Andreas Burchert Andreas Neubauer Dietrich Beelen Andreas Mackensen Nikolas von Bubnoff Wolfgang Herr Burkhard Becher Gerard Socié Michael A Caligiuri Eliana Ruggiero Chiara Bonini Georg Häcker Justus Duyster Jürgen Finke Erika Pearce Bruce R Blazar Robert Zeiser

Nat Med 2018 03 12;24(3):282-291. Epub 2018 Feb 12.

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

Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD leukemia cells. This synergized with the allogeneic CD8 T cell response, leading to long-term survival in six mouse models of FLT3-ITD AML. Sorafenib-related IL-15 production caused an increase in CD8CD107aIFN-γ T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8 T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.
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http://dx.doi.org/10.1038/nm.4484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029618PMC
March 2018

Successful outcome following allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency.

Blood 2018 02 26;131(8):917-931. Epub 2017 Dec 26.

Institute of Immunity and Transplantation, University College London (UCL), London, United Kingdom.

The primary immunodeficiencies (PIDs), rare inherited diseases characterized by severe dysfunction of immunity, have been successfully treated by allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in childhood. Controversy exists regarding optimal timing and use of Allo-HSCT in adults, due to lack of experience and previous poor outcomes. Twenty-nine consecutive adult patients, with a mean age at transplant of 24 years (range, 17-50 years), underwent Allo-HSCT. Reduced-intensity conditioning (RIC) included fludarabine (Flu)/melphalan/alemtuzumab (n = 20), Flu/busulfan (Bu)/alemtuzumab (n = 8), and Flu/Bu/antithymocyte globulin (n = 1). Stem cell donors were matched unrelated donors or mismatched unrelated donors (n = 18) and matched related donors (n = 11). Overall survival (OS), event-free survival, transplant-related mortality (TRM), acute and chronic graft-versus-host disease incidence and severity, time to engraftment, lineage-specific chimerism, immune reconstitution, and discontinuation of immunoglobulin replacement therapy were recorded. OS at 3 years for the whole cohort was 85.2%. The rarer PID patients without chronic granulomatous disease (CGD) achieved an OS at 3 years of 88.9% (n = 18), compared with 81.8% for CGD patients (n = 11). TRM was low with only 4 deaths observed at a median follow-up of 3.5 years. There were no cases of early or late rejection. In all surviving patients, either stable mixed chimerism or full donor chimerism were observed. At last follow-up, 87% of the surviving patients had no evidence of persistent or recurrent infections. Allo-HSCT is safe and effective in young adult patients with severe PID and should be considered the treatment of choice where an appropriate donor is available.
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http://dx.doi.org/10.1182/blood-2017-09-807487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225386PMC
February 2018

Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation.

Sci Transl Med 2017 Nov;9(416)

Regenerative Medicine, Division of Cancer Studies and Cancer Research UK King's Health Partners, King's College London, London SE5 9NU, UK.

The immunosuppressive activity of mesenchymal stromal cells (MSCs) is well documented. However, the therapeutic benefit is completely unpredictable, thus raising concerns about MSC efficacy. One of the affecting factors is the unresolved conundrum that, despite being immunosuppressive, MSCs are undetectable after administration. Therefore, understanding the fate of infused MSCs could help predict clinical responses. Using a murine model of graft-versus-host disease (GvHD), we demonstrate that MSCs are actively induced to undergo perforin-dependent apoptosis by recipient cytotoxic cells and that this process is essential to initiate MSC-induced immunosuppression. When examining patients with GvHD who received MSCs, we found a striking parallel, whereby only those with high cytotoxic activity against MSCs responded to MSC infusion, whereas those with low activity did not. The need for recipient cytotoxic cell activity could be replaced by the infusion of apoptotic MSCs generated ex vivo. After infusion, recipient phagocytes engulf apoptotic MSCs and produce indoleamine 2,3-dioxygenase, which is ultimately necessary for effecting immunosuppression. Therefore, we propose the innovative concept that patients should be stratified for MSC treatment according to their ability to kill MSCs or that all patients could be treated with ex vivo apoptotic MSCs.
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http://dx.doi.org/10.1126/scitranslmed.aam7828DOI Listing
November 2017

Gene therapy for Wiskott-Aldrich syndrome in a severely affected adult.

Blood 2017 09 17;130(11):1327-1335. Epub 2017 Jul 17.

Institute of Child Health, University College London, London, United Kingdom.

Until recently, hematopoietic stem cell transplantation was the only curative option for Wiskott-Aldrich syndrome (WAS). The first attempts at gene therapy for WAS using a ϒ-retroviral vector improved immunological parameters substantially but were complicated by acute leukemia as a result of insertional mutagenesis in a high proportion of patients. More recently, treatment of children with a state-of-the-art self-inactivating lentiviral vector (LV-w1.6 WASp) has resulted in significant clinical benefit without inducing selection of clones harboring integrations near oncogenes. Here, we describe a case of a presplenectomized 30-year-old patient with severe WAS manifesting as cutaneous vasculitis, inflammatory arthropathy, intermittent polyclonal lymphoproliferation, and significant chronic kidney disease and requiring long-term immunosuppressive treatment. Following reduced-intensity conditioning, there was rapid engraftment and expansion of a polyclonal pool of transgene-positive functional T cells and sustained gene marking in myeloid and B-cell lineages up to 20 months of observation. The patient was able to discontinue immunosuppression and exogenous immunoglobulin support, with improvement in vasculitic disease and proinflammatory markers. Autologous gene therapy using a lentiviral vector is a viable strategy for adult WAS patients with severe chronic disease complications and for whom an allogeneic procedure could present an unacceptable risk. This trial was registered at www.clinicaltrials.gov as #NCT01347242.
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http://dx.doi.org/10.1182/blood-2017-04-777136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813727PMC
September 2017

Dendritic Cells Cross-Present Immunogenic Lentivector-Encoded Antigen from Transduced Cells to Prime Functional T Cell Immunity.

Mol Ther 2017 02;25(2):504-511

Institute for Immunity and Transplantation, University College London, London NW3 2PF, UK; Cancer Institute, University College London, London WC1E 6DD, UK. Electronic address:

Recombinant lentiviral vectors (LVs) are highly effective vaccination vehicles that elicit protective T cell immunity in disease models. Dendritic cells (DCs) acquire antigen at sites of vaccination and migrate to draining lymph nodes, where they prime vaccine-specific T cells. The potency with which LVs activate CD8 T cell immunity has been attributed to the transduction of DCs at the immunization site and durable presentation of LV-encoded antigens. However, it is not known how LV-encoded antigens continue to be presented to T cells once directly transduced DCs have turned over. Here, we report that LV-encoded antigen is efficiently cross-presented by DCs in vitro. We have further exploited the temporal depletion of DCs in the murine CD11c.DTR (diphtheria toxin receptor) model to demonstrate that repopulating DCs that were absent at the time of immunization cross-present LV-encoded antigen to T cells in vivo. Indirect presentation of antigen from transduced cells by DCs is sufficient to prime functional effector T cells that control tumor growth. These data suggest that DCs cross-present immunogenic antigen from LV-transduced cells, thereby facilitating prolonged activation of T cells in the absence of circulating LV particles. These are findings that may impact on the future design of LV vaccination strategies.
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http://dx.doi.org/10.1016/j.ymthe.2016.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5368353PMC
February 2017

Impact of Pretransplantation (18)F-Fluorodeoxyglucose-Positron Emission Tomography on Survival Outcomes after T Cell-Depleted Allogeneic Transplantation for Hodgkin Lymphoma.

Biol Blood Marrow Transplant 2016 07 14;22(7):1234-1241. Epub 2016 Apr 14.

Department of Haematology, University College London Hospitals NHS Trust, London, United Kingdom; Department of Haematology, University College London Cancer Institute, London, United Kingdom. Electronic address:

Pretransplant (18)F-fluorodeoxyglucose (FDG) positron emission tomography status is an important prognostic factor for outcomes after autologous stem cell transplantation (SCT) in Hodgkin lymphoma (HL), but its impact on outcomes after allogeneic SCT remains unclear. We retrospectively evaluated outcomes after T cell-depleted allogeneic SCT of 116 patients with nonprogressive HL according to pretransplant Deauville scores. Endpoints were overall survival (OS), progression-free survival (PFS), relapse rate (RR), and nonrelapse-related mortality (NRM). OS, PFS, and RR did not differ significantly between the Deauville 1 to 2 and Deauville 3 to 5 cohorts (OS: 77.5% versus 67.3%, P = .49; PFS: 59.4% versus 55.7%, P = .43; RR: 20.9% versus 22.6%, P = .28 at 4 years). Differences in PFS remained statistically nonsignificant when comparisons were made between Deauville 1 to 3 and Deauville 4 to 5 cohorts (60.9% versus 51.4%, P = .10), and RR remained very similar (21.5% versus 23.8%, P = .42). Multivariate analyses demonstrated trends toward significance for an effect of Deauville score on PFS (hazard ratio 1.82 for Deauville 4 to 5, P = .06) and for number of lines of prior therapy on OS (hazard ratio 2.34 for >5 lines, P = .10). The latter effect appeared to be driven by higher NRM rather than increased RR. Our findings suggest that Deauville score before allogeneic SCT in patients with nonprogressive HL has a relatively modest impact on survival outcomes in comparison with the impact in autologous SCT and that predictive values for the individual patient remain low, indicating that residual FDG-avid disease should not preclude allogeneic SCT. Furthermore, our findings bring into question the importance of attainment of metabolic complete response in this setting if it is at the expense of increasing NRM risk.
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http://dx.doi.org/10.1016/j.bbmt.2016.03.034DOI Listing
July 2016

Expression of a dominant T-cell receptor can reduce toxicity and enhance tumor protection of allogeneic T-cell therapy.

Haematologica 2016 Apr 22;101(4):482-90. Epub 2016 Jan 22.

Institute of Immunity and Transplantation, UCL Division of Infection and Immunity, University College London, Royal Free Hospital London

Due to the lack of specificity for tumor antigens, allogeneic T-cell therapy is associated with graft-versus-host disease. Enhancing the anti-tumor specificity while reducing the graft-versus-host disease risk of allogeneic T cells has remained a research focus. In this study, we demonstrate that the introduction of 'dominant' T-cell receptors into primary murine T cells can suppress the expression of endogenous T-cell receptors in a large proportion of the gene-modified T cells. Adoptive transfer of allogeneic T cells expressing a 'dominant' T-cell receptor significantly reduced the graft-versus-host toxicity in recipient mice. Using two bone marrow transplant models, enhanced anti-tumor activity was observed in the presence of reduced graft-versus-host disease. However, although transfer of T-cell receptor gene-modified allogeneic T cells resulted in the elimination of antigen-positive tumor cells and improved the survival of treated mice, it was associated with accumulation of T cells expressing endogenous T-cell receptors and the development of delayed graft-versus-host disease. The in-vivo deletion of the engineered T cells, mediated by endogenous mouse mammary tumor virus MTV8 and MTV9, abolished graft-versus-host disease while retaining significant anti-tumor activity of adoptively transferred T cells. Together, this study shows that the in-vitro selection of allogeneic T cells expressing high levels of a 'dominant' T-cell receptor can lower acute graft-versus-host disease and enhance anti-tumor activity of adoptive cell therapy, while the in-vivo outgrowth of T cells expressing endogenous T-cell receptors remains a risk factor for the delayed onset of graft-versus-host disease.
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http://dx.doi.org/10.3324/haematol.2015.132712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004405PMC
April 2016

Depletion of CD11c⁺ cells in the CD11c.DTR model drives expansion of unique CD64⁺ Ly6C⁺ monocytes that are poised to release TNF-α.

Eur J Immunol 2016 Jan 30;46(1):192-203. Epub 2015 Nov 30.

Institute for Immunity and Transplantation, University College London, London, UK.

Dendritic cells (DCs) play a vital role in innate and adaptive immunities. Inducible depletion of CD11c(+) DCs engineered to express a high-affinity diphtheria toxin receptor has been a powerful tool to dissect DC function in vivo. However, despite reports showing that loss of DCs induces transient monocytosis, the monocyte population that emerges and the potential impact of monocytes on studies of DC function have not been investigated. We found that depletion of CD11c(+) cells from CD11c.DTR mice induced the expansion of a variant CD64(+) Ly6C(+) monocyte population in the spleen and blood that was distinct from conventional monocytes. Expansion of CD64(+) Ly6C(+) monocytes was independent of mobilization from the BM via CCR2 but required the cytokine, G-CSF. Indeed, this population was also expanded upon exposure to exogenous G-CSF in the absence of DC depletion. CD64(+) Ly6C(+) monocytes were characterized by upregulation of innate signaling apparatus despite the absence of inflammation, and an increased capacity to produce TNF-α following LPS stimulation. Thus, depletion of CD11c(+) cells induces expansion of a unique CD64(+) Ly6C(+) monocyte population poised to synthesize TNF-α. This finding will require consideration in experiments using depletion strategies to test the role of CD11c(+) DCs in immunity.
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http://dx.doi.org/10.1002/eji.201545789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722854PMC
January 2016

Genetic Regulation of Fate Decisions in Therapeutic T Cells to Enhance Tumor Protection and Memory Formation.

Cancer Res 2015 Jul 22;75(13):2641-52. Epub 2015 Apr 22.

Department of Haematology, Cancer Institute, University College London, London, United Kingdom. Institute of Immunity and Transplantation, University College London, London, United Kingdom.

A key challenge in the field of T-cell immunotherapy for cancer is creating a suitable platform for promoting differentiation of effector cells while at the same time enabling self-renewal needed for long-term memory. Although transfer of less differentiated memory T cells increases efficacy through greater expansion and persistence in vivo, the capacity of such cells to sustain effector functions within immunosuppressive tumor microenvironments may still be limiting. We have therefore directly compared the impact of effector versus memory differentiation of therapeutic T cells in tumor-bearing mice by introducing molecular switches that regulate cell fate decisions via mTOR. Ectopic expression of RAS homolog enriched in brain (RHEB) increased mTORC1 signaling, promoted a switch to aerobic glycolysis, and increased expansion of effector T cells. By rapidly infiltrating tumors, RHEB-transduced T cells significantly reduced the emergence of immunoedited escape variants. In contrast, expression of proline-rich Akt substrate of 40 kDa (PRAS40) inhibited mTORC1, promoted quiescence, and blocked tumor infiltration. Fate mapping studies following transient expression of PRAS40 demonstrated that mTORC1(low) T cells made no contribution to initial tumor control but instead survived to become memory cells proficient in generating recall immunity. Our data support the design of translational strategies for generating heterogeneous T-cell immunity against cancer, with the appropriate balance between promoting effector differentiation and self-renewal. Unlike pharmacologic inhibitors, the genetic approach described here allows for upregulation as well as inhibition of the mTORC1 pathway and is highly selective for the therapeutic T cells without affecting systemic mTORC1 functions.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-3283DOI Listing
July 2015

G-CSF mobilizes CD34+ regulatory monocytes that inhibit graft-versus-host disease.

Sci Transl Med 2015 Apr;7(281):281ra42

INSERM U1163 and CNRS ERL 8254, Faculté de Médecine, Université Paris Descartes, Hôpital Necker, 75015 Paris, France. Institut Hospitalo-Universitaire Imagine, Université Sorbonne Paris Cité, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France. Service d'Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, 75012 Paris, France. INSERM UMRs 938, Centre de recherche de l'hôpital Saint Antoine, 75012 Paris, France. Université Pierre et Marie Curie, Paris VI, 75006 Paris, France.

Granulocyte colony-stimulating factor (G-CSF) is routinely used to collect peripheral blood stem cells (PBSCs) from healthy donors for allogeneic hematopoietic stem cell transplantation (allo-HSCT). We show that, in both humans and mice, G-CSF mobilizes a subset of CD34(+) cells with mature monocyte features. These cells, which are phenotypically and functionally conserved in mice and humans, are transcriptionally distinct from myeloid and monocytic precursors but similar to mature monocytes and endowed with immunosuppressive properties. In response to interferon-γ released by activated T cells, these cells produce nitric oxide, which induces allogeneic T cell death both in vitro and in vivo. These apoptotic T cells are engulfed by macrophages that release transforming growth factor-β and promote regulatory T cell expansion. Indeed, the fraction of CD34(+) monocytes in peripheral blood CD34(+) cells inversely correlates with the incidence of acute graft-versus-host disease (GVHD) in humans. Therefore, G-CSF-mobilized cells are an attractive candidate population to be expanded ex vivo for cellular therapy against GVHD.
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http://dx.doi.org/10.1126/scitranslmed.3010435DOI Listing
April 2015

CD8 T cell tolerance to a tumor-associated self-antigen is reversed by CD4 T cells engineered to express the same T cell receptor.

J Immunol 2015 Feb 24;194(3):1080-9. Epub 2014 Dec 24.

Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom;

Ag receptors used for cancer immunotherapy are often directed against tumor-associated Ags also expressed in normal tissues. Targeting of such Ags can result in unwanted autoimmune attack of normal tissues or induction of tolerance in therapeutic T cells. We used a murine model to study the phenotype and function of T cells redirected against the murine double minute protein 2 (MDM2), a tumor-associated Ag that shows low expression in many normal tissues. Transfer of MDM2-TCR-engineered T cells into bone marrow chimeric mice revealed that Ag recognition in hematopoietic tissues maintained T cell function, whereas presentation of MDM2 in nonhematopoietic tissues caused reduced effector function. TCR-engineered CD8(+) T cells underwent rapid turnover, downmodulated CD8 expression, and lost cytotoxic function. We found that MDM2-TCR-engineered CD4(+) T cells provided help and restored cytotoxic function of CD8(+) T cells bearing the same TCR. Although the introduction of the CD8 coreceptor enhanced the ability of CD4(+) T cells to recognize MDM2 in vitro, the improved self-antigen recognition abolished their ability to provide helper function in vivo. The data indicate that the same class I-restricted TCR responsible for Ag recognition and tolerance induction in CD8(+) T cells can, in the absence of the CD8 coreceptor, elicit CD4 T cell help and partially reverse tolerance. Thus MHC class I-restricted CD4(+) T cells may enhance the efficacy of therapeutic TCR-engineered CD8(+) T cells and can be readily generated with the same TCR.
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http://dx.doi.org/10.4049/jimmunol.1401703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298128PMC
February 2015

CMV promotes recipient T-cell immunity following reduced-intensity T-cell-depleted HSCT, significantly modulating chimerism status.

Blood 2015 Jan 12;125(4):731-9. Epub 2014 Dec 12.

Department of Haematology, University College London Cancer Institute, London, United Kingdom; Department of Haematology, University College London Hospital, London, United Kingdom; and.

Cytomegalovirus (CMV) remains a significant cause of morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). Clinical risk varies according to a number of factors, including recipient/donor CMV serostatus. Current dogma suggests risk is greatest in seropositive recipient (R+)/seronegative donor (D-) transplants and is exacerbated by T-cell depletion. We hypothesized that in the setting of reduced-intensity T-cell-depleted conditioning, recipient-derived CMV-specific T cells escaping deletion may contribute significantly to CMV-specific immunity and might therefore also influence chimerism status. We evaluated 105 recipients of alemtuzumab-based reduced-intensity HSCT and collated details on CMV infection episodes and T-cell chimerism. We used CMV-specific HLA multimers to enumerate CMV-specific T-cell numbers and select cells to assess chimerism status in a subset of R+/D- and R+/seropositive donor patients. We show that in R+/D- patients, CMV-specific T cells are exclusively of recipient origin, can protect against recurrent CMV infections, and significantly influence the chimerism status toward recipients. The major findings were replicated in a separate validation cohort. T-cell depletion in the R+/D- setting may actually, therefore, foster more rapid reconstitution of protective antiviral immunity by reducing graft-vs-host directed alloreactivity and the associated elimination of the recipient T-cell compartment. Finally, conversion to donor chimerism after donor lymphocytes is associated with clinically occult transition to donor-derived immunity.
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http://dx.doi.org/10.1182/blood-2014-07-589150DOI Listing
January 2015

OX40- and CD27-mediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence.

J Immunol 2015 Jan 17;194(1):125-133. Epub 2014 Nov 17.

Transplantation Immunology Group, Cancer Institute and Institute for Immunity and Transplantation, University College London.

Exhaustion of chronically stimulated CD8(+) T cells is a significant obstacle to immune control of chronic infections or tumors. Although coinhibitory checkpoint blockade with anti-programmed death ligand 1 (PD-L1) Ab can restore functions to exhausted T cell populations, recovery is often incomplete and dependent upon the pool size of a quiescent T-bet(high) subset that expresses lower levels of PD-1. In a model in which unhelped, HY-specific CD8(+) T cells gradually lose function following transfer to male bone marrow transplantation recipients, we have explored the effect of shifting the balance away from coinhibition and toward costimulation by combining anti-PD-L1 with agonistic Abs to the TNFR superfamily members, OX40 and CD27. Several weeks following T cell transfer, both agonistic Abs, but especially anti-CD27, demonstrated synergy with anti-PD-L1 by enhancing CD8(+) T cell proliferation and effector cytokine generation. Anti-CD27 and anti-PD-L1 synergized by downregulating the expression of multiple quiescence-related genes concomitant with a reduced frequency of T-bet(high) cells within the exhausted population. However, in the presence of persistent Ag, the CD8(+) T cell response was not sustained and the overall size of the effector cytokine-producing pool eventually contracted to levels below that of controls. Thus, CD27-mediated costimulation can synergize with coinhibitory checkpoint blockade to switch off molecular programs for quiescence in exhausted T cell populations, but at the expense of losing precursor cells required to maintain a response.
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http://dx.doi.org/10.4049/jimmunol.1401644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272895PMC
January 2015

OX40- and CD27-mediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence.

J Immunol 2015 Jan 17;194(1):125-133. Epub 2014 Nov 17.

Transplantation Immunology Group, Cancer Institute and Institute for Immunity and Transplantation, University College London.

Exhaustion of chronically stimulated CD8(+) T cells is a significant obstacle to immune control of chronic infections or tumors. Although coinhibitory checkpoint blockade with anti-programmed death ligand 1 (PD-L1) Ab can restore functions to exhausted T cell populations, recovery is often incomplete and dependent upon the pool size of a quiescent T-bet(high) subset that expresses lower levels of PD-1. In a model in which unhelped, HY-specific CD8(+) T cells gradually lose function following transfer to male bone marrow transplantation recipients, we have explored the effect of shifting the balance away from coinhibition and toward costimulation by combining anti-PD-L1 with agonistic Abs to the TNFR superfamily members, OX40 and CD27. Several weeks following T cell transfer, both agonistic Abs, but especially anti-CD27, demonstrated synergy with anti-PD-L1 by enhancing CD8(+) T cell proliferation and effector cytokine generation. Anti-CD27 and anti-PD-L1 synergized by downregulating the expression of multiple quiescence-related genes concomitant with a reduced frequency of T-bet(high) cells within the exhausted population. However, in the presence of persistent Ag, the CD8(+) T cell response was not sustained and the overall size of the effector cytokine-producing pool eventually contracted to levels below that of controls. Thus, CD27-mediated costimulation can synergize with coinhibitory checkpoint blockade to switch off molecular programs for quiescence in exhausted T cell populations, but at the expense of losing precursor cells required to maintain a response.
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http://dx.doi.org/10.4049/jimmunol.1401644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272895PMC
January 2015

An unexpected role for platelets in blocking Th17 differentiation.

J Clin Invest 2014 Feb 27;124(2):480-2. Epub 2014 Jan 27.

It is well known that platelets interact with cells of the innate immune system to promote tissue repair. In contrast, it is less clear whether these links extend to cells of the adaptive immune system, such as T cells. In this issue of the JCI, Morrell and colleagues provide compelling evidence that platelets are required to limit CD4+ Th17 differentiation through the actions of the chemokine platelet factor 4 (PF4). Absence of PF4 in the host leads to exaggerated Th17 differentiation after transplantation and rapid graft rejection. The authors' findings argue that platelets are not bit part players, but rather fully fledged, critical members of the adaptive immune system.
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http://dx.doi.org/10.1172/JCI74231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904637PMC
February 2014

Cell-intrinsic regulation of murine dendritic cell function and survival by prereceptor amplification of glucocorticoid.

Blood 2013 Nov 30;122(19):3288-97. Epub 2013 Sep 30.

School of Immunity and Infection, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom;

Although the inhibitory effects of therapeutic glucocorticoids (GCs) on dendritic cells (DCs) are well established, the roles of endogenous GCs in DC homeostasis are less clear. A critical element regulating endogenous GC concentrations involves local conversion of inactive substrates to active 11-hydroxyglucocorticoids, a reduction reaction catalyzed within the endoplasmic reticulum by an enzyme complex containing 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and hexose-6-phosphate dehydrogenase (H6PDH). In this study, we found that this GC amplification pathway operates both constitutively and maximally in steady state murine DC populations and is unaffected by additional inflammatory stimuli. Under physiologic conditions, 11βHSD1-H6PDH increases the sensitivity of plasmacytoid DCs (pDCs) to GC-induced apoptosis and restricts the survival of this population through a cell-intrinsic mechanism. Upon CpG activation, the effects of enzyme activity are overridden, with pDCs becoming resistant to GCs and fully competent to release type I interferon. CD8α(+) DCs are also highly proficient in amplifying GC levels, leading to impaired maturation following toll-like receptor-mediated signaling. Indeed, pharmacologic inhibition of 11βHSD1 synergized with CpG to enhance specific T-cell responses following vaccination targeted to CD8α(+) DCs. In conclusion, amplification of endogenous GCs is a critical cell-autonomous mechanism for regulating the survival and functions of DCs in vivo.
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http://dx.doi.org/10.1182/blood-2013-03-489138DOI Listing
November 2013

Risk-stratified adoptive cellular therapy following allogeneic hematopoietic stem cell transplantation for advanced chronic lymphocytic leukaemia.

Br J Haematol 2013 Mar 7;160(5):640-8. Epub 2013 Jan 7.

Royal Free Hampstead NHS Trust, London, UK.

Following reduced intensity-conditioned allogeneic stem cell transplantation (RIC allo-SCT) for chronic lymphocytic leukaemia (CLL), there is an inverse relationship between relapse and extensive chronic graft-versus-host disease (GVHD). We evaluated outcomes in 50 consecutive patients with CLL using the approach of alemtuzumab-based RIC allo-SCT and pre-emptive donor lymphocyte infusions (DLI) for mixed chimerism or minimal residual disease (MRD), with the intention of reducing the risk of GVHD. Forty two patients had high-risk disease, including 30% with 17p deletion (17p-). Of patients who were not in complete remission (CR) entering transplant, 83% subsequently achieved MRD-negative CR. Both MRD detection and uncorrected mixed chimerism were associated with greater risks of treatment failure. Nine of sixteen patients receiving DLI for persistent or relapsed disease subsequently attained MRD-negative CR. With a median follow-up of 4.3 years, 4-year current progression-free survival was 65% and overall survival was 75% (60% and 61% in respectively, patients with 17p-). DLI was associated with a 29% cumulative incidence of severe GVHD and mortality of 6.4%. At last follow-up, 83% of patients in CR were off all immunosuppressive treatment. In conclusion, the directed delivery of allogeneic cellular therapy has the potential to induce durable remissions in high-risk CLL without incurring excessive GVHD.
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http://dx.doi.org/10.1111/bjh.12197DOI Listing
March 2013

Dendritic cells in tissues: in situ stimulation of immunity and immunopathology.

Trends Immunol 2012 Jan 24;33(1):8-13. Epub 2011 Oct 24.

Department of Haematology, Division of Cancer Studies, UCL Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.

Dendritic cells (DCs) prime and orchestrate naïve T cell immunity in lymphoid organs, but recent data also highlight the importance of DC-effector T cell interactions in tissues. These studies suggest that effector T cells require a second activating step in situ from tissue DCs to become fully competent for effector functions and/or proliferation and survival. DC stimulation of effector T cells within tissues has evolved as a mechanism to ensure that T cells are activated to their full potential only at the site of ongoing infection. Here, we propose that under conditions of uncontrolled inflammation and release of tissue antigens, the same DC-dependent checkpoint perpetuates a destructive response and immunopathology.
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http://dx.doi.org/10.1016/j.it.2011.09.008DOI Listing
January 2012