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It has to be a summary as you will put it in a PowerPoint. the presentation will be 10 minutes long so it has to be the most important about the article. Also, I need to use the figures that are there or similarly to explain the concept. The class is about all cancer, so it has to be a focus on immunotherapy with CAE-T cell in cancers. Thank you
324 © Royal College of Physicians 2018. All rights reserved.ORIGINAL RESEARCH Clinical Medicine CME HAEMATOLOGY Clinical Medicine 20 21081 V7o Vl o18l 1, 7N, oN 4o: 63:2 342–48–8Authors: A clinical research fellow, King’s College London, London,UK ; B national medical director’s clinical fellow, NHS England, UK ;C consultant haematologist, King’s College Hospital NHS FoundationTrust, London, UK ; D professor of stem cell transplantation, King’sCollege London, London, UK; E consultant haematologist, King’sCollege Hospital NHS Foundation Trust, London, UKAuthors: Charlotte Graham, A Rebecca Hewitson, B Antonio PagliucaC ,D and Reuben Benjamin ECellular therapy is a key tool to treat haematologicalmalignancies. Over 40,000 allogeneic and autologoushaematopoietic stem cell transplants (HSCTs) are performedannually across Europe. 1 Since 2017, a new T cell therapy,chimeric antigen receptor-T (CAR-T) cells have been licensedoutside clinical trials. CAR-T cells have extremely potentantitumour activity, but also have a profile of toxic sideeffects not seen before. Cytokine release syndrome (CRS)and CAR-T cell-related encephalopathy syndrome (CRES)are common, predictable and potentially lethal side effects.Patients frequently require admission to intensive care, andmanagement from a number of medical specialties. Thisexciting and powerful new therapy requires the formationof new multispecialty medical teams for safe delivery and tosuccessfully manage the resultant complications.IntroductionCellular therapy is well established, with the first published caseseries of blood transfusion reported in 1824 by the obstetricianJames Blundell. 2 Although many of his patients died, presumablyin part due to ABO incompatibility, he demonstrated the principlethat cells transferred from one individual to another could carry outtheir life-sustaining functions. Over a century later, the first successfulhaematopoietic stem cell transplant (HSCT) was performed betweenidentical twins. With human leucocyte antigen (HLA) typing thistherapy was extended to HLA matched siblings and unrelateddonors, but a new condition graft-versus-host disease (GVHD) wasobserved, whereby donor-derived T-cells attack the recipient. 3Alongside these pivotal moments in transplantation history, itwas increasingly recognised that our immune system detects andeliminates cancer cells. Tumour-infiltrating lymphocytes takenfrom melanoma patients and grown in the laboratory couldcause tumour regression when infused back. 4 Allogeneic HSCT isnow known to not only provide a rescue bone marrow followingchemotherapy, but to actually treat leukaemia via the graft versusleukaemia effect (GVL). To enhance GVL, additional lymphocytesABSTRACTCancer immunotherapy with CAR-T cells – behold the futureKey pointsThe intensive care team is crucial to enable successful delivery ofCAR-T cell therapy within a JACIE-accredited BMT facilityCRS is common and patients can develop multiorgan failureTociluzimab, an IL-6 receptor antagonist, is given to patientswith severe CRS, and corticosteroids are reserved for patients notresponding to tociluzimabNeurotoxicity/CRES can result in seizures and cerebral oedemaAntiepileptics and steroids may be used to treat neurotoxicityKEYWORDS: CAR-T cells, cytokine release syndrome,cancer immunotherapy, cellular therapy, CAR-T cell-relatedencephalopathy syndrome ■can be collected from HSCT donors and given to their recipientpatients (donor lymphocyte infusions), but failures occur. This isbecause cancer cells hide from the immune system by reducingHLA expression (required for T-cells to detect them) and disablethe immune system by upregulating inhibitory molecules (immunecheckpoints).T-cells have been genetically engineered to overcome theseobstacles resulting in a new therapy, CAR-T cells. However, like thefirst acute haemolytic transfusion reactions and GVHD, they bringwith them a unique set of toxic complications that physicians needto recognise and manage.Chimeric antigen receptor-T cellsT cells are collected from patients or healthy donors andgenetically modified to express an artificial receptor. Patients thenreceive chemotherapy, prior to CAR-T cell infusion, which depletesimmunosuppressive cells thereby aiding CAR-T cell expansion.The extracellular domain of the CAR derives from a monoclonalantibody (usually the single chain variable fragment) which bindsto antigens on cancer cells (see Fig 1 ). Binding initiates signallingin the intracellular domain, CD3ζ (the downstream signallingcomponent of a normal T-cell receptor) and a costimulatorydomain (usually 4-1BB or CD28) that allows the T-cells to havesustained antitumour activity. The concept was first developedby Eshhar in the 1980s, 5 but is now globally revolutionising how© Royal College of Physicians 2018. All rights reserved. 325CME Haematologyhaemato-oncologists treat patients, with the first two CAR-T cellproducts licensed by the FDA in 2017. 6The success of this therapy in B-cell malignancies isunprecedented. Adult B-acute lymphoblastic leukaemia (B-ALL)patients relapsing post allograft have a median survival of ∼7months. 7 Following CAR-T cell therapy >80% of relapsed andrefractory patients achieved a complete remission (CR), 8–12resulting in 50–86% of patients being alive 1 year later. 11,12Similarly, B-cell lymphoma patients with chemorefractory diseasehave a median survival of just 6.3 months. 13 More than 50%were in CR following CAR-T cells, 14,15 with more than half alive 18months post infusion. 14 A proportion of patients are expectedto achieve a long-term remission, although relapses do occur.Reduced expression of the target antigen on tumour cells andrejection of CAR-T cells are known mechanisms of resistance.Numerous other CAR-T cells are being evaluated in clinical trialsfor haematological and solid organ malignancies with somepromising early data for myeloma. 16 The responses in some keytrials are summarised in Table 1 .Both licensed products target CD19, an antigen expressed onB-cells. Tisagenlecleucel, brought to market by Novartis, andAxicabtagene Ciloleucel, developed by Kite Pharma / Gilead,are indicated for B-ALL and B-cell lymphoma respectively. TheEuropean Medicines Agency (EMA) are reviewing both products,and a decision is expected imminently.However, these new treatments have potentially lethal side effects(see Fig 2 ). CAR-T cells have created a novel list of complicationsin patients receiving them. The most significant, cytokine releasesyndrome (CRS) and CAR-T cell-related encephalopathy syndrome(CRES), require expertise from a range of medical specialties.Currently, it is known that some patients will succumb to thesecomplications. There is a pressing need for improved understandingand management of these iatrogenic conditions.Cytokine release syndromeCRS is the most commonly seen and expected life-threateningcomplication following CAR-T cell infusion. Indeed, the absenceTable 1. Summary data of key clinical trials of CAR-T cellsClinical trial Patient group Objectiveresponse rateCompleteremission rateOverall survival ReferenceELIANA(Novartis)Children and youngadults with relapsed andrefractory B-ALL81% 81% Median survival 19.1 months 11MSKCC Adults with relapsed B-ALL − 83% Median survival 12.9 months 12ZUMA-1(Kite Pharma)Adults with refractory largeB-cell lymphoma82% 54% 52% at 18 months 14JULIET(Novartis)Adults with relapsed DLBCLor follicular lymphoma64% 43% DLBCL 71%follicular lymphomaDLBLC median survival 22.2 months,follicular lymphoma not reached15CRB-401 (Bluebirdbio / Celgene)Relapsed and refractorymultiple myeloma89% 22% Not available 16B-ALL = B-acute lymphoblastic leukaemia; DLBCL = diffuse large B-cell lymphomaCAR-T cellCosmulatorydomainSingle chainvariablefragmentCD19 angen on B cellmalignanciesCD3ζBinding of CARconstructIntracellular signallingcascade in CAR-T cell Killing of tumour cellB cellFig 1. Schematic diagram ofCAR-T cells.326 © Royal College of Physicians 2018. All rights reserved.CME HaematologyCAR-T cell-related encephalopathy syndromeCRES ranges from mild confusion to fatal cerebral oedema.Typically, patients develop an encephalopathy with dysphasia anddisorientation. Seizures can occur, as can focal motor symptoms. 18In some but not all patients experiencing these symptoms, CAR-Tcells have been detected in the cerebrospinal fluid (CSF). 18 Thepathophysiology is not fully understood.Fundoscopic examination for papilloedema, and neuroimagingwith computed tomography (CT) / magnetic resonance imaging(MRI) should be carried out. 18 If it can be performed safely, alumbar puncture measuring CSF pressure should be done. Theincidence of seizures is high and an electroencephalogram (EEG)is indicated in those with CRES. One group found non-convulsivestatus epilepticus in 10% of patients who received CAR-T cells. 17However, the severity and frequency of CRES varies betweendifferent CAR-T cell products.In those with raised intracranial pressure, high-dosecorticosteroids should be initiated. Other therapies aimedat lowering intracranial pressure should be trialled, includingacetazolamide, hyperosmolar therapy, and hyperventilation inliaison with neurosurgical and neuro-ITU teams. 17 If seizure-likeactivity is seen on EEG, antiepileptics are indicated. 18 If statusepilepticus is present benzodiazepines are given with furtherspecialist input from neurology. In those receiving CAR-T cellproducts associated with CRES prophylactic antiepileptics shouldbe considered. 17Challenges of delivering CAR-T cell therapyHospitals delivering CAR-T cell therapy need to establish amultidisciplinary team, with an education programme andexpertise in managing the complications of this therapy. NHSEngland are currently developing service specifications for bothproducts and centres will be assessed against these. Centreswill need to be JACIE (Joint Accreditation Committee-ISCT &EBMT) accredited bone marrow transplant (BMT) units. Alongsidehaematologists, intensivists are vital. Neurologists, cardiologistsand renal physicians should also be part of these specialist teams(see Fig 3 ).of CRS raises concern that CAR-T cells are failing to expandsufficiently to eradicate the malignant cells. In clinical trials ofthe licensed products, it occurred in 57–97% of patients, 11,14,15leading to 47% of patients in one study requiring admission tointensive therapy unit (ITU). 11 Each agent has its own specifictoxicity profile.CRS is a state of immune over-activation. CAR-T cells receivean exaggerated signal through the artificial receptor stimulatingthem to secrete cytokines. This activates other cells of theimmune system, including macrophages and drives expansion ofinfused CAR-T cells. IL-6, IFN-γ and IL-10 are typically elevated.This activates other cells of the immune system, includingmacrophages and drives expansion of infused CAR-T cells. IL-6 atvery high levels is thought to directly cause some organ toxicityseen in CRS although the exact pathophysiology is still beingelucidated.Fever is an early sign. Patients can rapidly develop multisystemcomplications including: acute respiratory distress syndrome (ARDS),acute kidney injury (AKI), liver failure, disseminated intravascularcoagulation (DIC), cardiomyopathy and arrhythmias. 17 Therehave been cases of patients with severe CRS developing fulminanthaemophagocytic lymphohistiocytosis (HLH), a serious conditionwith a similar pattern of immune over-activation. 17Serum ferritin and C-reactive protein (CRP) are typically elevatedsupporting a diagnosis of CRS. Cytokine levels, if available, provideadditional diagnostic information. The current managementstrategy follows a step-wise approach. Mild CRS with fever istreated with paracetamol and fluid hydration. Intravenous(IV) antibiotics are given to cover the differential diagnosis ofneutropaenic sepsis. Hypotension is treated with an IV fluid bolus.If patients require repeated fluid boluses or inotropes to maintaintheir blood pressure then specific IL-6 blocking therapy should beconsidered. Tociluzimab, an IL-6 receptor antagonist, is approved bythe FDA for severe CRS; 6 it has shown good efficacy, with 69% ofpatients having recovered at 2 weeks. 6 In patients not respondingto tociluzimab, or in whom organ dysfunction has developed, ashort course of corticosteroids should be given. 17 Patients withsevere CRS should be managed within the ITU with appropriateorgan support.Fig 2. Organ dysfunctionfollowing CAR-T cell therapy.Liver: hepac failureSkin: rashesRenal: acute kidney injuryCardiac: stress-inducedcardiomyopathy, arrhythmias,cardiac arrestNeurological: dysphasia,confusion, seizures, cerebraloedemaHaematological: coagulopathy,cytopaenias, haemophagocyc,lymphohisocytosisRespiratory: acuterespiratory distress syndrome© Royal College of Physicians 2018. All rights reserved. 327CME HaematologyDelivery of therapy should be coordinated with intensive carewho are aware of all CAR-T cell patients and alerted at the time ofcell infusion. Complications tend to follow a predictable timeline(although this varies between CAR-T cell products), helping toinform bed-planning decisions. Once patients develop early CRS,ITU should be updated regularly, with outreach team review, sothat patients are transferred at the appropriate time. With theplanned establishment of cell therapy units which include intensivecare beds it is hoped patient care and survival of complications willimprove.ConclusionsCellular therapy and cancer immunotherapy are now firmlypositioned at the forefront of anticancer treatment. Patientswith chemorefractory disease are accessing new, geneticallyengineeredT cell therapies, particularly CAR-T cells. As thesetreatments move into the mainstream, physicians will encounterand be expected to manage the resultant complications. Newteams, consisting of haematologists, intensivists and othermedical specialists, need to be established to allow successfuldelivery of these powerful new treatments. ■Conflicts of interestCharlotte Graham receives research funding from Servier and hasreceived funding to attend educational meetings from Gileadand Pfizer. Antonio Pagliuca has received advisory board fees forNovartis and Bluebird BIO, clinical input into the KCH Cellectis trialand is the National Clinical Lead for Regenerative Medicine NHSE.Reuben Benjamin receives research funding from Servier and Pfizer,participated in advisory board meetings for Servier, Pfizer, Novartisand Gilead, and is principal investigator of a Servier sponsored CAR-Tcell trial.References1 Passweg JR , Baldomero H , Bader P et al . Hematopoietic stem celltransplantation in Europe 2014: more than 40,000 transplantsannually . Bone Marrow Transplant 2016 ; 51 ; 786 – 92 .2 Blundell J. Researches Physiological and Pathological . London :E. Cox Co. Sons , 1824 .3 Thomas ED . A history of haemopoietic cell transplantation .Br J Haematol 1999 ; 105 : 330 – 9 .4 Dudley ME , Wunderlich JR , Robbins PF et al . Cancer regression andautoimmunity in patients after clonal repopulation with antitumorlymphocytes . Science 2002 ; 298 : 850 – 4 .5 Gross G , Waks T , Eshhar Z . Expression of immunoglobulin T-cellreceptor chimeric molecules as functional receptors withantibody-type specificity . Proc Natl Acad Sci USA1989 ; 86 : 10024 – 8 .6 US Food & Drug Administration . FDA approves tisagenlecleucelfor B-cell ALL and tociluzimab for cytokine release syndrome . FDA ,2017 . www.fda.gov/drugs/informationondrugs/approveddrugs/ucm574154.htm [Accessed 26 February 2018] .7 Kantarjian H , Stein A , Gökbuget N et al . Blinatumomab versuschemotherapy for advanced acute lymphoblastic leukaemia .N Engl J Med 2017 ; 376 : 836 – 47 .8 Brentjens RJ , Rivière I , Park JH et al . Safety and persistence ofadoptively transferred autologous CD19-targeted T cells in patientswith relapsed or chemotherapy refractory B-cell leukemias . Blood2011 ; 118 : 4817 – 28 .HaematologyJACIE-accreditedBMT unitsIntensive CareMedicineRenalMedicinePalliaveCareCardiology PsychiatryDermatologyNeurosurgeryNeurologyFig 3. Key teams involvedin the delivery of CAR-Tcell therapy.328 © Royal College of Physicians 2018. All rights reserved.CME Haematology9 Grupp SA , Kalos M , Barrett D et al . Chimeric antigen receptormodifiedT cells for acute lymphoid leukemia . N Engl J Med2013 ; 368 : 1509 – 18 .10 Maude SL , Frey N , Shaw PA et al . Chimeric antigen receptorT cells for sustained remissions in leukaemia . N Engl J Med2014 ; 371 : 1507 – 17 .11 Maude SL , Laetsch TW , Buechner J et al . Tisagenlecleucel inchildren and young adults with B-cell lymphoblastic leukaemia .N Engl J Med 2018 ; 378 : 439 – 48 .12 Park JH , Riviere I , Gonen M et al . Long-term follow-up of CD19CAR therapy in acute lymphoblastic leukaemia . N Engl J Med2018 : 378 : 449 – 59 .13 Crump M , Neelapu SS , Farooq U et al . Outcomes in refractorydiffuse large B-cell lymphoma: results from the internationalSCHOLAR-1 study . Blood 2017 ; 130 : 1800 – 8 .14 Neelapu SS , Locke FL , Bartlett N et al . Axicabtagene ciloleucel CART-Cell therapy in refractory large b-cell lymphoma . N Engl J Med2017 ; 377 : 2531 – 44 .15 Schuster SJ , Svoboda J , Chong E et al . Chimeric antigen receptor T cellsin refractory B-cell lymphomas . N Engl J Med 2017; 377: 2545– 54.16 Berdeja JG , Lin Y , Raje N et al . Durable clinical responses in heavilypretreated patients with relapsed/refractory multiple myeloma:updated results from a multicentre study of bb2121 anti-BcmaCAR T cell therapy . Blood 2017 : 130 ( Suppl 1 ): 740 .17 Neelapu SS , Tummala S , Kebriaei P et al . Chimeric antigen receptorT-cell therapy assessment and management of toxicities . Nat RevClin Onc 2018 ; 15 : 47 – 62 .18 Davila ML , Riviere I , Wang X et al . Efficacy and toxicity managementof 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia .Sci Transl Med 2014; 6: 224ra25.Address for correspondence: Dr Charlotte ElizabethGraham, King’s College London, Haematological Medicine,123 Coldharbour Lane, London SE5 9NU, UK.Email: charlottegraham@nhs.net
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