Currentopinionin immunology.
`v. 21, no. 2 (Apr. 2009)
`General Collection
`W1 CU799GDL
`2009-06-19 11:42:08
`
`Volume 21, issue @» April 2009
`ISSN Qo52-/915
`
`- a ae
`
`Frederick Alt & Philippa Marrack, Editors
`
`‘April 2009
`
`june 2009 Lymphocyte activation and effector functions * Vaccines
`August 2009 Host-pathogens « Immune senescence
`October 2009 Primary immunodeficiencies * Immunogenetics and transplantation
`December 2009 Autoimmunity * Allergy and hypersensitivity
`February 2010 Innate immunity * Antigen processing
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`CURRENT
`OPINION
`|
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`Miltenyi Ex. 1007 Page 1
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`Miltenyi Ex. 1007 Page 1
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`Current Opinionin 1
`Editors Frederick Alt
`
`mmunology
`usa Philippa Marrack usa
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`Volume 21 (2009)
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`2009 Contents
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`February
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`Innate immunity
`Edited by Siamon Gordon and Giorgio Trinchieri
`Antigen processing
`Edited by Hidde Ploegh and Sebastian Amigorena
`
`April
`
`Lymphocyte development
`Edited by Casey Weaver and Alexander Rudensky
`Tumour immunology
`Edited by Ton Schumacher and Nick Restifo
`
`June
`activation and effector
`Lymphocyte
`functions
`Edited by Michael McHeyzer-Williams and
`Miche! Nussenzweig
`Vaccines
`Edited by Greg Poland and Alan Barrett
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`August
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`Host-pathogens
`Edited by Michael Brenner and Robert Modlin
`Immune senescence
`Edited by Susan Swain and Ken Dorshkind
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`October
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`Primary immunodeficiencies
`Edited by Jean-Laurent Casanova and
`Luigi Notarangelo
`Immunogenetics and transplantation
`Edited by Andrea Velardi and Frank Christiansen
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`December
`
`Autoimmunity
`Edited by Jeffrey Bluestone and Vijay Kuchroo
`Allergy and hypersensitivity
`Edited by Marc Rothenberg and Marc Daeron
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`'ee
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`ELSEVIER
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`Miltenyi Ex. 1007 Page 3
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`

` Available online at www.sciencedirect.com
`
`“°° ScienceDirect
`
`Volume 21, issue 2, April 2009
`
`Current Opinion in
`
`
`
`Immunology
`
` Abstracted/indexed in: BIOSIS, CAB Abstracts International, CAB Health, Chemical Abstracts, EMBASE,Index Medicus,
`Medline. Also coveredin the abstract andcitation database SCOPUS"™.Full text available on ScienceDirect®
`
`
`CONTENTS
`
`Lymphocyte development
`Edited by Casey Weaver and Alexander Rudensky
`
`119
`
`Casey T Weaver and Alexander Y Rudensky
`Editorial overview
`
`Reviews
`J Jeremiah Bell, Daniel A Zlotoff and
`121
`Anthony W Chi,
`Avinash Bhandoola
`Untangling the T branch of the hematopoiesis tree
`
`479
`
`Alison Crawford and E John Wherry
`The diversity of costimulatory and inhibitory receptor pathways
`and the regulation of antiviral T cell responses
`
`Tumour immunology
`Edited by Ton Schumacher and Nick Restifo
`
`487.
`
`Ton NM Schumacherand Nicholas P Restifo
`Editorial overview: Adoptive T cell therapy of cancer
`
`Reviews
`190
`Rienk Offringa
`Antigen choice in adoptive T-cell therapy of cancer
`
`200
`
`209
`
`215
`
`224
`
`Pawel Muranski and Nicholas P Restifo
`Adoptive immunotherapy of cancer using CD4* T cells
`Gavin M Bendle,
`John BAG Haanen and Ton NM
`Schumacher
`Preclinical development of T cell receptor gene therapy
`Michel Sadelain, Renier Brentjens and Isabelle Riviere
`The promise and potential pitfalls of chimeric antigen receptors
`Carolina Berger, Cameron J Turtle, Michael C Jensen and
`Stanley R Riddell
`Adoptive transfer of virus-specific and tumor-specific T cell
`immunity
`
`233
`
`Steven A Rosenberg and Mark E Dudley
`Adoptive cell therapy for the treatmentof patients with metastatic
`melanoma
`
`
`The Cover
`Premalignant lesions in a mouse model for adoptive T cell therapy of
`Ester MM van Leeuwen,
`prostate carcinoma. The figure showsthe developmentof early lesions in
`Charles D Surh
`prostate sections of TRAMP mice as revealed by staining with an antibody
`Generation and maintenance of memory CD4* T Cells
`specific for the SV40large T antigen. Administration of engineeredTcells
`specific for the SV40 antigen has been shown to highly reduce disease
`173
`Tracy C Kuo and Mark S Schlissel
`progressionin this preclinical model for adoptive T cell therapy. (Courtesy
`Mechanisms controlling expression of the RAG locus during
`of Ton Schumacher, NKI, Amsterdam.)
`lymphocyte development
`
`127
`
`133
`
`440
`
`146
`
`153.
`
`161
`
`167
`
`Ichiro Taniuchi
`Transcriptional
`decision
`
`regulation in helper versus cytotoxic-lineage
`
`Michael S Krangel
`Mechanics of T cell receptor gene rearrangement
`
`Kirk DC Jensen and Yueh-hsiu Chien
`Thymic maturation determines 8 T cell function, but not their
`antigen specificities
`
`Liang Zhou and Dan R Littman
`Transcriptional regulatory networks in Th17 cell differentiation
`Charalampos
`G_
`Spilianakis
`and
`
`Derk Amsen,
`Richard A Flavell
`How are T,,1 and T,,2 effector cells made?
`Adewole $ Adamson, Kalonji Collins, Arian Laurence and
`John J O'Shea
`The Current STATus of lymphocyte signaling: new roles for old
`players
`
`Jonathan
`
`Sprent
`
`and
`
`DO! 10.1016/S0952-7915(09)00059-4
`
`Miltenyi Ex. 1007 Page 4
`
`Miltenyi Ex. 1007 Page 4
`
`

`

`
`
`Available online at www.sciencedirect.com
`
`“2° ScienceDirect
`
`Current Opinion in
`
`Immunology
`
`The next issue of this journal
`
`Lymphocyte activation and effector functions
`Edited by Michael McHeyzer-Williams and
`Michel Nussenzweig
`
`Mike Carroll
`Complement and Immune regulation
`
`Dan Stetson
`Trex and autoimmunity
`
`Michael McHeyzer-Williams
`TFH as a regulator of B cell responses
`
`Jeff Bluestone
`Dynamic transition of CD4+ Foxp3 T cells
`
`Casey Weaver
`Th 17 differentiation
`
`Sue Kaech
`Effector/memory CD8s
`
`Jason Cysler
`B cell responses
`
`Antonio Lanzavecchia
`B cell memory in humans
`
`Vaccines
`Edited by Greg Poland and Alan Barrett
`
`Tom Richie and Sofia Casares
`Candidate malaria vaccines
`
`Alan Barrett
`The immunology of yellow fever vaccine-based adverse events
`
`Greg Poland
`Second generation tuberculosis vaccines
`
`Linda Lambert
`Why are HSN1 vaccine antigens poorly immunogenic?
`
`Ennio De Gregorio
`The immunology of vaccine adjuvants
`
`Greg Glenn
`Transcutaneous immunization and the role of dendritic cells
`
`Peter Doherty and Steve Turner
`CD8T cell activation and TCR repertoire
`
`Hiroshi Kiyono
`Mucosal vaccines and immunology
`
`DOI 10.1016/S0952-7915(09)00060-0
`
`Miltenyi Ex. 1007 Page 5
`
`Miltenyi Ex. 1007 Page 5
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`

`

`Available online at www.sciencedirect.com
`india a
`
`°»” ScienceDirect
`
` i
`
`
`ELSEVIE
`Adoptive transfer of virus-specific and tumor-specific T cell
`immunity
`Carolina Berger’, Cameron J Turtle’, Michael C Jensen? and
`Stanley R Riddell’
`
`The adoptive transfer of T cells isolated or engineered to have
`obstacle for applying T cell therapy to human malignan-
`specificity for diseased cells represents an ideal approach for
`cies would be the requirement to isolate and expand
`the targeted therapy of human viral and malignant diseases.
`tumor-reactive Tcells to sufficient numbers to modulate
`The therapeutic potential of adoptive T cell therapy for
`‘T’ cell immunity. The identification of tumor associated
`infections and cancer was demonstrated in rodent models long
`antigens (TAA) and refined culture techniques have
`ago, but the task of translating this approach into aneffective
`overcome this obstacle for selected tumors such as mel-
`clinical therapy has not been easy. Carefully designed clinical
`anoma. However,in initial studies the infusion of large
`trials have evaluated the transfer of antigen-specific T cells in
`numbers of I’ cells orl cell clones specific forTAAfailed
`humans, and provided insight into the barriers to efficacy and
`to completely eradicate tumors in the majority of
`strategies to improveTcell therapy. The importanceofaltering
`patients, at least in part due to the short persistence of
`the host environmentto facilitate persistence and function of
`the transferred T cells jn vivo [6-9]. ‘This review will
`transferred T cells andintrinsic properties of T cells that are
`summarize insights that have been derivedfromclinical
`selected or engineered for therapyin determining their fate in
`trials of T’ cell immunotherapythat have led to progress
`vivo are key issues that have recently emerged and are
`in developing improved regimens for establishing a
`informing the design of the next generationof clinicaltrials.
`durable and functional T cell response using adoptive
`Addresses
`T cell transfer.
`‘D3-100, Fred Hutchinson Cancer Research Center, 1100 Fairview
`Avenue NE, Seattle, WA, United States
`* City of Hope National Medical Center, Duarte, CA, United States
`
`Corresponding author: Berger, Carolina (cberger@fherc.org), Turtle,
`Cameron J (cturtle@fherc.org), Jensen, Michael C (mjensen@coh.org)
`and Riddell, Stanley R (sriddell@fherc.org)
`
`Current Opinion in Immunology 2009, 21:224-239
`
`This review comes from a themed issue on
`Tumour Immunology
`Edited by Ton Schumacher and Nick Restifo
`
`Available online 21st March 2009
`
`0952-7915/$ — see front matter
`© 2009 Elsevier Ltd. All rights reserved.
`
`DOI 10.1016/j.coi.2009.02.010
`
`T cell therapy for opportunistic virus
`infections and virus induced malignancy
`A notable success of adoptive T cell transfer is its use to
`prevent or treat opportunistic virus infections in allo-
`gencic hematopoietic stem cell transplant (HCT)recipi-
`ents. Regimens for HCT often employ myeloablative
`doses of chemotherapyand radiation to treat the under-
`lying malignancy and facilitate engraftment of donor stem
`cells, and either administer immunosuppressive drugs
`post transplant or deplete T cells from the donor stem
`cell graft to prevent graft-versus-host disease (GVHD)
`[10]. These treatments result in a prolonged functional
`and/or numerical deficic of T cells, and render HCT
`recipients susceptible to life-threatening infection, both
`from endogenous latent viruses that reactivate afterHCT
`and from acute community acquired viruses.
`
`Cytomegalovirus
`Introduction
`Reactivation of latent cytomegalovirus (CMV) in allo-
`An intact and functional Tcell compartmentis critical for
`geneic HCT recipients remains a significant cause of
`effective immunityto pathogens and there is evidence
`morbidity and mortality despite antiviral drug therapy
`that Tcells can participate in the control andelimination
`[11]. The finding that progressive infection with CMV
`of tumors [1,2]. Studies in rodent models of cancer and
`correlated with deficient CMV-specific CD8* and CD4*
`infectious diseases have demonstrated that the adoptive
`T cell responses suggested that the adoptive transfer of
`transfer of ‘T’ cells of defined antigen specificity can
`CMV-specific T cells isolated from the immunocompe-
`establish or augment immunityand eradicate malignant
`tent donor mightbe used to restore protective immunity
`or infected cells. Adoptive T cell transfer also has thera-
`in the recipient. The initial studies of adoptive immu-
`peutic activity against human viral
`infections in allo-
`notherapy for CMVinfused CD8* 'T cell clones or poly-
`gencic hematopoietic stem cell transplant recipients, a
`clonal ‘T cell lines that were derived from the donor and
`setting in which virus-specific T cells can be readily
`selected for recognition ofCMV-infected cells and lack of
`isolated and expanded from the immunocompetent
`cross reactivity with recipient alloantigens [5,12,13]. The
`donor [3-5]. It wasinitially perceived that the major
`enrichmentand cloning of CMV-specific T cells required
` Current Opinion in Immunology 2009, 21:224-232
`www.sciencedirect.com
`
`This material may be protected by Copyright law (Title 17 U.S. Code) Miltenyi Ex. 1007 Page 6
`
`Miltenyi Ex. 1007 Page 6
`
`

`

`Adoptive transfer of virus-specific and tumor-specific T cell immunity Berger et al.
`
`225
`
`Figure 1
`
`
`Targetcell
`
`ARRRRRARRRRRRRRARABRAAR
`RRRRR
`
`ANYMSUE
`
`:
`TCR
`ee)
`MHC/peptide 6
`is(GC
`
`
`ARRRARARRBRARARRSARA
`WAVBUSES BEBE
`
`
`
`Disruption of
`TCRsignaling
`
`|
`
`\
`
`\/
`
`eo"Nucleus
`
`SR
`
`Geneinduction/repression
`
`Current Opinion in Immunology
`
`
`prolonged culture but avoided a risk of GVHD, which is
`observed frequently if unselected donor T cells are
`administered to HCTrecipients. ‘These studies demon-
`strated that CD8* and CD4* CMV-specific T cells could
`be adoptively transferred to patients earlyafter HCTwith
`minimal
`toxicity, and that
`the transferred cells could
`persist and function i vwo, and control
`infection
`[5,12,13].
`
`the complex culture
`Despite this encouraging data,
`methods used to isolate CMV-specific T cells limited
`the broad and timelyapplication ofthis approach. More
`recent efforts have been directed at designing methods to
`select CMV-specific T cells directly from donor blood.
`Immunomagnetic selection of antigen-specific T cells has
`been developed based onbindingoftetrameric HLA class
`I molecules folded with CMVpeptides, or the capture of T
`cells that secrete interferon gamma after antigen stimu-
`lation [14,15]. The infusion of remarkably small numbers
`of donor-derived CD8* Tcells selected for binding to HLA
`class I tetramers containing CMVpp65 or [E-1 peptides to
`allogeneic HC'Trecipients with CMVreactivation restored
`T cell responses to these CMVantigens and reduced the
`need for antiviral drug therapy[3].
`
`
`
`
`
`Glucocorticoids exert negative effects on adoptively transferred T cells
`through both nongenomic and genomic mechanisms. The non-ligated
`glucocorticoid receptor (GR)is associated with the T cell receptor
`Adoptive T cell therapy for CMVis not uniformly suc-
`signaling complexes containing Fyn and Lck. Immediately upon binding
`cessful
`in protecting HCT recipients from progressive
`of the GR to glucocorticoid (GC), these multiprotein complexes are
`CMVinfection.
`It
`is
`increasingly clear that adoptive
`disrupted leadingtofailure of downstream signalingafter engagementof
`the TCR by antigen. Binding of GC to the GRin the cytoplasm also leads
`transfer of CMV-specific T cells is ineffective in patients
`to translocation of the bound receptor to the nucleus and regulation of a
`that require high doses of glucocorticoidstotreat GVHD,
`numberof glucocorticoid responsive genes, including repression of
`which occurs in at least 35% of HLAidentical allogeneic
`proinflammatory genes suchasIL-2, and activation of
`HCTrecipients that receive a non Tcell depleted stem
`immunosuppressive genes such as MAPK phosphatase-1, and
`interleukin 10.
`cell graft
`[16]. Glucocorticoids impair ‘T cell antigen
`nn—.
`receptorsignaling and cytokine production, and promote
`Tcell apoptosis, and these effects are mediated through
`bindingto the glucocorticoid receptor (GR), activation of
`GR-responsive immunosuppressive genes and inhibition
`of proinflammatorygenes[17,18] (Figure 1). Nongenomic
`effects of the GR in T cells have also been described,
`including a physical interaction of unligated GR with the
`TCR complex, which is disrupted by glucocorticoid bind-
`Epstein Barr virus
`ing resulting in impaired activation of Lek and Fyn [19]
`Severely immunocompromisedsolid organ and HCT reci-
`(Figure 1). Thus, patients that receive prolonged treat-
`pients, particularly those that receive a T cell depleted
`ment with glucocorticoids have frequentreactivations of
`HCT or T cell depleting antibodies to treat GVHDor
`CMVand are at highrisk of toxicity from antiviral drugs
`organ graft rejection, may develop an Epstein Barr virus
`and for the development of drugresistantviral variants. In
`driven lymphoproliferative disease (EBV-LPD), consist-
`a clinical trial at the Fred Hutchinson Cancer Research
`ing of EBV-infected B cells that express the highly immu-
`Center, the infusion of CD8* and CD4* CMV-specific T
`nogenic EBNA-3A, 3B, and 3C proteins. Rooney and
`cell clones failed to restore persistent functional T cell
`colleagues haveisolated polyclonal EBV-specific T cells
`immunityin patients that received prednisone, and these
`containing variable numbers of CD8* and CD4 Tcells
`patients remained at risk forCMVviremia. These results
`from the blood of HC'Tdonors byrepeated 7” vitro sumu-
`suggest that glucocorticoids will be useful for reversing
`lation with EBVtransformedB cell lines that express the
`toxicity that might develop after adoptive T’ cell therapy
`EBNAproteins, and administered these T cells to the
`but pose a problem for
`reconstituting virus-specific
`respective recipients with EBV-LPDorat highrisk for
`immunity in HCTrecipients. T cells can be engineered
`EBV-LPD. Adoptive T cell therapy targeting EBV was
`to be resistant to glucocorticoids by interfering with GR
`highly effective, both for promoting tumor regression in
`expression by introduction of siRNA or by gene editing
`
`Current Opinion in Immunology 2009, 21 224-232
`www,sciencedirect.com
`
`with zinc finger nucleases [20]. The latter approachis now
`being evaluated in animal models, and may enable the
`restoration of a protective glucocorticoid resistant CMV-
`specific T cell responsein this high-risk group of patients.
`
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`226 Tumour Immunology
`
`patients with established EBV-LPD and preventing the
`development of LPD when used as prophylaxis [4,21]
`
`reconstitution to the most prevalent viral pathogens after
`HCT.
`
`EBV-LPD can be rapidly progressive and similar to the
`situation with CMV,
`the time required to isolate and
`expand EBV-reactive ‘Tcells is a significant obstacle to
`the routine use of adoptive Tcell therapy. Several groups
`are developing cryopreserved banks of polyclonal EBV-
`specific Tcells from HLA typed volunteer donors so that
`a cell product could be immediately available to treat
`severe EBVinfections in unrelated transplantrecipients.
`The initial results of infusing partially HLA matched
`EBV-specific T cell lines to immunocompromised solid
`organ allograft recipients with EBV-LPD are surprisingly
`encouraging, both in terms of safety and therapeutic
`efficacy [22°]. The degree of immunodeficiency in the
`recipient is apparently sufficiently severe that the allo-
`geneic T cells are not rejected before mediating anti-
`tumoractivity.
`
`EBVis also associated with a number of malignancies that
`occur
`in immunocompetent
`individuals. A subset of
`Hodgkin’s disease contains EBV genomes and express
`a limited number of weakly immunogenic EBVproteins,
`including LMP-2. Bollard er a/. have used dendritic cells
`engineered to express LMP-2 as antigen presenting cells
`to expand autologous LMP-2-specific T cells
`from
`patients with Hodgkin's disease [23]. The adoptive trans-
`fer of polyclonal T cells containing both CD4* and CD8*
`LMP-2specific Tcells augmented LMP-2 specific T cell
`immunity and promoted tumor regression in a subset of
`these patients [23]. Studies are alsoin progress to develop
`adoptive T’ cell therapy for the subset of nasopharyngeal
`carcinomas that are EBVpositive [24].
`
`T cell therapy for non-opportunistic
`persistent viruses
`Theefficacyof adoptive Tcell therapyfor viral infections
`in immunocompromisedhosts raises the prospect of using
`T’ cell therapy to boost partially effective responses to
`human immunodeficiency, hepatitis C, and hepatitis B
`viruses that cause a chronic persistent infection, Early
`efforts to boost HIV-specific CD8* T cell responses by
`adoptive transfer were unsuccessful due to short-term
`persistence of the transferred T cells in individuals with
`replicating virus [28]. We now knowthat CD8* and CD4*
`virus-specific ‘T cells in these chronic infections are
`characterized by a progressive loss of function and via-
`bility related to upregulation of inhibitory molecules such
`as PD-1 and Tim-3 [29-31]. ‘Thus, the infusion of au-
`tologous T cells engineered to recognize these viruses by
`introduction of virus-specific TCR genes [32,33], com-
`bined with inhibitors of PD-1 or Tim-3 signaling path-
`ways might improve the quantity and functionofantiviral
`T cells. This strategy maycarrya risk of immunopathol-
`ogy, particularly if the antigen load is excessive at the
`time ‘T’ cell therapy is administered. An approachthatis
`being developed to restore the CD4 deficiency in HIV
`infection is
`to engineer autologous CD4 Tcells for
`adoptive transfer that lack the CCR-5 co-receptor for
`HIVentry using zine finger nucleases to permanently
`disrupt the CCR-5 coding sequence [34°"],
`
`Tumor-specific T cell therapy
`Adoptive ‘T’ cell therapy for human malignancyhas pro-
`ven to be more challenging and less effective than for
`opportunistic
`viral
`infections. This
`reflects
`several
`Other opportunistic viruses
`obstacles, such as the difficulty isolating the rare highly
`Effective drug therapy is not available for several other
`avid T’ cells that are specific for self-antigens expressed
`viruses that cause morbidity after allogeneic HCT and
`selectively or preferentially by tumor cells from most
`might be amenable to adoptive 'Tcell therapy, including
`cancer patients;
`the
`requirement
`that
`transferred
`adenovirus, community respiratory viruses, and BK virus
`tumor-reactive T’ cells persist iv vivo,
`traffic to tumor
`[25,26]. Our knowledge concerning the antigen speci-
`sites and function in an inhospitable immunosuppressive
`ficity and protective capacity of T cell responses to these
`tumor microenvironment; and the potential for antigen or
`viruses in humans is incomplete, and the frequencyof T
`HLAloss tumorcells variants to escape recognition [35—
`cells in donor blood is typically much lowerthanfor latent
`38]. As a consequence, even when tumor-reactive T cells
`viruses such as CMVand EBV. Nevertheless, efforts are
`have been isolated and expanded from cancer patients,
`being made to derive T cell products that contain an
`the adoptive transfer of these cells to treat malignancy
`expanded repertoire of virus specificities and could be
`was usually unsuccessful, and understanding the precise
`used in adoptive therapy. Leen e a/. have developed a
`reasons for failure posed a formidable task. A proximal
`culture method in which a recombinant adenovirus that
`problem that was evidentin the initial trials, and one that
`encodes the CMVpp65 protein is used to infect EBV-
`was distinct from the results of T cell therapy for viral
`LCL for use in stimulating T cells from HCT donors
`infections after HCT was that the persistence of adop-
`[27°]. This results in the simultaneous expansion of T
`tively transferred tumor-specific T cells in vivo was
`cells specific for adenovirus, CMV and EBV, and the
`remarkably short [6,8,9], The basis for the differential
`infusion ofsuch ‘T’ cells into HCT recipients augmented
`persistence of adoptivelytransferred virus-specific T cells
`responses to all three viruses and promoted virus clear-
`in HCT recipients and tumor-reactive Tcells in cancer
`ance. It is likely that additional viral antigens could be
`patients is now being revealed, and reflects both the
`incorporated into such culture systems to hasten immune
`environment
`into which the T cells are infused and
`
`Current Opinion in Immunology 2009, 21:224-232
`www.sciencedirect.com
`
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`Adoptive transfer of virus-specific and tumor-specific T cell immunity Berger et a/.
`
`227
`
`qualitative attributes of ‘I’ cells that are isolated and
`expanded for adoptive transfer.
`
`Depletion of endogenous lymphocytes to improve the
`efficacy of adoptively transferred tumor-specific T cells
`The longest persistence of adoptivelytransferred T cells
`in humans was observed when virus-specific T cells were
`administered to immunodeficient allogeneic HCT reci-
`pients early post-transplant, when lymphopenia is typi-
`cally present [3-5]. Although notinitially recognized, a
`lymphopenic environment maycontribute significantly to
`improving the persistence of transferred T cells by redu-
`cing competition for cytokines such as IL15 and IL.7 that
`pr