CD8+ cytotoxic T lymphocytes isolated from allogeneic healthy donors recognize HLA class Ia/Ib–associated renal carcinoma antigens with ubiquitous or restricted tissue expression

Dörrschuck, Andreas; Schmidt, Andrea; Schnürer, Elke; Glückmann, Matthias; Albrecht, Christian; Wölfel, Catherine; Lennerz, Volker; Lifke, Alexander; Natale, Carmela Di; Ranieri, Elena; Gesualdo, Loreto; Huber, Christoph; Karas, Michael; Wölfel, Thomas; Herr, Wolfgang

doi:10.1182/blood-2004-02-0459

Cited by 34 publications

(23 citation statements)

References 57 publications

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“…In one study that generated tumour-specific CD8 þ cytotoxic T cells from allogeneic donors, MLTCs were initiated with a highly purified population of CD8 þ donor lymphocytes potentially underestimating the role of CD4 þ clones in the immune response. (Dorrschuck et al, 2004). Our data are the first to document the results of cloning MHC class I and II HLA-matched allogeneic effector cells stimulated with whole tumour cells and are in line with previous observations made using autologous MLTC (Takahashi et al, 1995).…”

Section: Discussionsupporting

confidence: 90%

Generation of tumour-specific cytotoxic T-cell clones from histocompatibility leucocyte antigen-identical siblings of patients with melanoma

Gottlieb

Lionello

et al. 2006

Br J Cancer

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Lymphodepletion and infusion of autologous expanded tumour-infiltrating lymphocytes is effective therapy for patients with malignant melanoma. Antitumour responses are likely to be mediated by HLA class I-and II-restricted immune responses directed at tumour antigens. We assessed whether the peripheral blood of normal HLA-matched siblings of patients with melanoma could be used to generate lymphocytes with antimelanoma activity for adoptive immunotherapy after allogeneic blood or marrow transplantation. Melanoma cell lines were derived from two donors and were used to stimulate the mononuclear cells of three HLAidentical siblings. CD4 þ clones dominated cultures. Of these, approximately half were directly cytotoxic towards recipient melanoma cells and secreted interferon-g in response to tumour stimulation. More than half of the noncytotoxic clones also secreted interferong after melanoma stimulation. No CD4 þ clones responded to stimulation with recipient haemopoietic cells. The majority of CD8 þ clones directly lysed recipient melanoma, but did not persist in long-term culture in vitro. No crossreactivity with recipient haemopoietic cells was observed. The antigenic target of one CD4 þ clone was determined to be an HLA-DR11-restricted MAGE-3 epitope. Antigenic targets of the remaining clones were not elucidated, but appeared to be restricted through a non-HLA-DR class II molecule. We conclude that the blood of allogeneic HLA-matched sibling donors contains melanoma-reactive lymphocyte precursors directed at tumour-associated antigens. Adoptive immunotherapy with unselected or ex vivo-stimulated donor lymphocytes after allogeneic stem cell transplantation has a rational basis for the treatment of malignant melanoma.

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Section: Discussionsupporting

confidence: 90%

Generation of tumour-specific cytotoxic T-cell clones from histocompatibility leucocyte antigen-identical siblings of patients with melanoma

Gottlieb

Lionello

et al. 2006

Br J Cancer

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“…37 Acute myeloid leukemia (AML) blasts were harvested from peripheral blood of patients with leukemia with white blood cell counts exceeding 10 11 /L. Blasts were isolated by Ficoll density centrifugation and were stored in liquid nitrogen until use.…”

Section: Donors and Cell Linesmentioning

confidence: 99%

Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines

Wehler

Nonn

Brandt

et al. 2006

Blood

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IntroductionFor many patients with leukemia lacking a matched hematopoietic stem cell donor, transplantation of HLA-incompatible stem cells remains the only curative treatment option. 1 However, donorpatient disparities at single or multiple HLA alleles increase the risks of graft rejection or severe graft-versus-host disease (GVHD). [2][3][4][5][6][7] Both complications are mainly mediated by alloreactive T cells that recognize oligopeptides in association with foreign HLA molecules. 8,9 T-cell depletion (TCD) is an efficient means for reducing alloreactivity 10 and is mandatory if donors share only one HLA haplotype with the recipients. 11 In this haploidentical setting, however, rigorous TCD abrogates specific immunity against pathogens and leukemia cells resulting in higher mortality from infections and disease relapse. 12,13 The precursor frequency of alloreactive T cells is much higher than that of T cells recognizing infectious agents or malignant cells. [14][15][16] Thus, depletion strategies need to substantially reduce alloreactive T cells, while sparing antipathogen and antitumor specificities. Various selective allodepletion (SAD) approaches have been developed for this purpose. Most of them rely on the ex vivo stimulation of donor lymphocytes derived from peripheral blood or bone marrow samples against recipient alloantigenpresenting cells over 1 to 7 days. Activated alloreactive T cells are subsequently depleted either by concomitant costimulatory blockade 17 ; by photodynamic purging 18,19 ; by fluorescence-activated cell sorting 20,21 ; by CD95-mediated apoptosis 22 ; or by targeting the activation-induced antigens CD25, [23][24][25][26][27][28][29][30][31] CD71, and HLA-DR. 24 Two of these approaches already demonstrated in vivo efficacy in terms of GVHD reduction and graft survival in haploidentical transplantation. 17,32,33 However, disease relapse remained the major complication in patients receiving allodepleted grafts. This might be explained by the inadequately low precursor frequencies of leukemia-reactive T cells within infused lymphocytes.We describe herein an alternative approach that is based on the in vitro expansion of donor T-cell lines through repeated stimulations with allogeneic leukemia or tumor cells prior to SAD. Because responding T cells durably expressed high levels of CD25, CD69, and CD95, we searched for alternative activation-induced antigens suitable for the allodepletion step. Among several candidates tested, the tumor necrosis factor receptor superfamily member CD137 (4-1BB) 34,35 demonstrated the most favorable expression kinetic in allostimulated T-cell cultures. Using immunomagnetic CD137 depletion reagents we obtained a 1-log reduction of anti-HLA mismatch specificities in T-cell lines stimulated with HLA-incompatible leukemia or tumor cells. Allodepleted cultures showed considerable residual antitumor and antiviral CD8 T-cell responses. We also introduce HLA-negative K562 cells 36 transfected with single HLA-class I molecules as an efficient tool to detect and d...

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“…22 ELIS-POT results are expressed as means of duplicates or triplicates analyzed for each experimental condition. To determine anti-HLA mismatch reactivity, K562 cells transfected with single HLA-class I alleles were used as antigen-presenting cells (APCs).…”

Section: Ifn-␥ Elispot Assaymentioning

confidence: 99%

Prophylactic transfer of CD8-depleted donor lymphocytes after T-cell–depleted reduced-intensity transplantation

Meyer¹,

Britten²,

Wehler³

et al. 2006

Blood

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Allogeneic hematopoietic stem cell transplantation (SCT) regimens incorporating the lymphocytotoxic CD52 antibody alemtuzumab demonstrate efficient engraftment and reduced graft-versus-host disease (GVHD). However, these protocols substantially impair posttransplantation antiviral and antitumor immunity. To accelerate immune reconstitution after alemtuzumab-based reduced-intensity SCT, we administered prophylactic CD8-depleted donor lymphocyte infusions (DLIs) starting on days 60 and 120 after transplantation. DLIs were processed in an immunomagnetic good manufacturing practice depletion procedure resulting in a 2.5-to 6-log reduction in CD8 T cells.

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CD8+ cytotoxic T lymphocytes isolated from allogeneic healthy donors recognize HLA class Ia/Ib–associated renal carcinoma antigens with ubiquitous or restricted tissue expression

Cited by 34 publications

References 57 publications

Generation of tumour-specific cytotoxic T-cell clones from histocompatibility leucocyte antigen-identical siblings of patients with melanoma

Generation of tumour-specific cytotoxic T-cell clones from histocompatibility leucocyte antigen-identical siblings of patients with melanoma

Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines

Prophylactic transfer of CD8-depleted donor lymphocytes after T-cell–depleted reduced-intensity transplantation

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