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  • 1
    Online-Ressource
    Online-Ressource
    Eradication of Medullary Multiple Myeloma by CD4+ Cytotoxic Human T Lymphocytes Directed at a Single Minor Histocompatibility Antigen
    American Association for Cancer Research (AACR) ; 2010
    In:  Clinical Cancer Research Vol. 16, No. 22 ( 2010-11-15), p. 5481-5488
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 22 ( 2010-11-15), p. 5481-5488
    Kurzfassung: Purpose: The essential role of CD4+ T cells as helpers of anticancer immunity is indisputable. Little is known, however, about their capacity to serve as effector cells in cancer treatment. Therefore, we explored the efficacy of immunotherapy with sole CD4+ cytotoxic human T cells directed at a hematopoietic-restricted minor histocompatibility antigen (mHag). Experimental Design: In macrophage-depleted Rag2−/−γc−/− mice, which were also devoid of T, B, and natural killer cells, mHag-specific native T cells or tetanus toxoid (TT)-specific T cells transduced with the mHag-specific T-cell receptor (TCR) were injected to treat full-blown mHag+ human multiple myeloma tumors. Results: mHag-specific antitumor responses were achieved after injection of native or mHag-TCR-transduced T cells. Although the therapy completely eradicated the primary tumors in the bone marrow, it failed to control extramedullary relapses, even after repeated T-cell injections. Detailed analyses ruled out mHag or MHC downregulation as mechanisms of extramedullary tumor escape. Impaired T-cell survival in vivo or defective homing to the tumor site were also ruled out as mechanisms behind extramedullary relapses, because injections of TT-loaded antigen presenting cells could facilitate homing of long-term surviving T cells to s.c. tumor sites. Moreover, intratumoral treatment of extramedullary tumors with 3AB11 was also ineffective. Conclusions: Taken together, these results for the first time show the feasibility of immunotherapy of primary bone marrow tumors with sole CD4+ human T cells directed to a tumor-associated mHag. Extramedullary relapses, probably due to microenvironment-dependent inhibitory mechanisms, remain a challenging issue towards effective cellular immunotherapy of hematologic malignancies. Clin Cancer Res; 16(22); 5481–8. ©2010 AACR.
    Materialart: Online-Ressource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-10-1340
    RVK:
    XA 36791
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2010
    ZDB Id: 1225457-5
    ZDB Id: 2036787-9
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    Online-Ressource
    Online-Ressource
    A Single Nucleotide Polymorphism in CD19 Defines a Novel Target for Immunotherapy of B Cell Malignancies with CD4+ Cytotoxic T Cells.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 1798-1798
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 1798-1798
    Kurzfassung: The Graft-versus-Tumor (GvT) effect of HLA-matched allogeneic stem cell transplantation (allo-SCT) is largely mediated by donor-derived alloreactive CD4+ and CD8+ T cells. Major targets of this curative effect are the minor Histocompatibility antigens (mHags) expressed on the malignant cells. Here we report the first mHag encoded by a hematopoietic gene and recognized by HLA class II (HLA-DQA1*05/B1*02)-restricted CD4+ T cells. This antigen is encoded by a single nucleotide polymorphism (SNP) in the B cell lineage-specific CD19 gene, a highly important target antigen for immunotherapy of almost all B cell malignancies. We identified this antigen using a novel and powerful genetic strategy, in which a phenotype-genotype correlation scanning was the key step for fine-mapping the genetic locus defined by pair-wise linkage analysis. In functional assays, CD4+ T cells specific for the CD19L-encoded mHag mediated effective peptide-dependent maturation of DCs and polarized them to produce significant levels of interleukin-12. In another assay, the CD19L-mHag-specific T cells facilitated the proliferation of a CD8+ mHag-specific T cell clone in an antigen-dependent manner. Even more important, they also lysed CD19L-positive malignant cells, illustrating the therapeutic advantages of targeting this CD19 L -derived, HLA class II-restricted mHag. The currently available immunotherapy strategies enable the exploitation of these therapeutic effects within and beyond allo-SCT settings.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.1798.1798
    RVK:
    XA 33000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2007
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    Online-Ressource
    Online-Ressource
    Induction of Potent Anti-Tumor Effects by Original and TCR-Redirected CD4 + Cytotoxic T Cells.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 1333-1333
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1333-1333
    Kurzfassung: Abstract 1333 Poster Board I-355 The curative Graft versus Tumor (GvT) effect of allogeneic stem cell transplantation and donor lymphocyte infusions is mainly mediated by donor derived T cells recognizing minor Histocompatibility antigens (mHag) presented by malignant cells. Traditionally, CD8+ cytotoxic T cells (CTLs) are considered as “the” effector cells of these anti-tumor responses, whereas a sole helper role is attributed to CD4+ T cells. CD4+ T cells often possess killer capacities in vitro, raising the possibility that they may also mediate anti-tumor effects without the need for CD8+ T cells. Hence, we here explored the feasibility of adoptive immunotherapy with sole CD4+ CTLs by testing the therapeutic capacity of a mHag-specific, CD4+ CTL (3AB11) in a human GvT model. Rag2−/−γc−/− mice were inoculated with BLI detectable, mHag+ Multiple myeloma cells. Treatment of established tumors with 3AB11 but not with control CD4+ T cells by triple consecutive injections of 30-40×106 cells/day rapidly reduced the medullary growing tumors, illustrating for the first time the feasibility to establish a significant GvT effect by targeting a sole mHag recognized by CD4+ CTLs. The therapy was less effective at a higher tumor load and unsuccessful by a single injection of 20×106 cells, underscoring the critical importance of T cell dose-to-tumor load ratio to establish an efficient anti-tumor effect. In further exploration, tumors were also significantly reduced by treatment with “dual antigen-specific” T cells, which were generated by transduction of the T cell receptor (TCR) of clone 3AB11 into recall antigen (Tetanus Toxoid; TT)-specific T cells. Finally, the in vivo persisting dual-specific T cells could be boosted by administration of TT loaded mHag negative B cells, demonstrating for the first time the feasibility and potential advantages of immunotherapy with TCR-transduced “dual antigen-specific” CD4+ T cells. We conclude that potent GvT effects may be achieved in clinical trials by targeting a sole mHag antigen with original or TCR-redirected CD4+ CTLs. Disclosures No relevant conflicts of interest to declare.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.1333.1333
    RVK:
    XA 33000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2009
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    Online-Ressource
    Online-Ressource
    Identification of Minor Histocompatibility Antigens Based on the 1000 Genomes Project for Application in Therapeutic Dendritic Cell Vaccination
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 2418-2418
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2418-2418
    Kurzfassung: Minor histocompatibility antigens (mHags) are highly immunogenic, HLA-bound polymorphic peptides playing prominent roles in the development of the graft vs host disease (GvHD) as well as the therapeutic graft vs tumor (GvT) effect of allogeneic stem cell transplantation (allo-SCT). To date, a small subset of mHags has been identified as genuinely hematopoietic system-specific. This small number of conceptually GvT-associated mHags are currently being tested in various clinical trials for the feasibility and efficacy of inducing an exclusive GvT effect without GvHD in patients with relapsing haematological malignancies after allo-SCT. Nonetheless, a broader and timely application of mHags as therapeutic tools in allo-SCT, as well as the development of appropriate GvHD prevention strategies still requires more insights that can be acquired through the identification of a much larger set of mHags presented by various HLA molecules in different ethnic populations. Recently, the introduction of genome-wide association (GWAS)-based strategies, despite a number of drawbacks, significantly accelerated the identification of mHags. To develop a strategy that can overcome the drawbacks of these earlier developed strategies, we now integrated our previously developed GWAS methodology [1,2] with the comprehensive genomic databases from the 1000 Genomes Project [3] . We show that the data set of the 1000 Genomes Project is suitable to identify all theoretical possible mHags, hereby enabling us to delineate important yet unknown characteristics of mHags. Furthermore, we demonstrate the actual power of this novel approach by the rapid and unambiguous identification of the HLA-DP4 restricted mHag UTDP4-1, which -despite extensive efforts in the past 15 years- could not be identified using any of the previously developed biochemical, molecular biological or genetic strategies. The 1000 Genomes Project-based identification of mHags thus represents a very rapid, convenient and robust method for the identification of new mHags, that will not only improve the understanding of the yet unknown facets of mHags but may also significantly enlarge the arsenal of targets for immunotherapy in haematological cancers. Spaapen et al., J.Exp.Med. 2008 Nov 24;205(12):2863-72. Oostvogels et al., Leukemia 2013 Mar;27(3):642-9. Abecasis et al., Nature 2012 Nov 1;491(7422):56-65. Disclosures Lokhorst: Celgene: Research Funding; J & J: Research Funding; Genmab: Research Funding. Mutis:Genmab BV: Research Funding; J & J: Research Funding; Celgene: Research Funding.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.2418.2418
    RVK:
    XA 33000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2014
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
    Online-Ressource
    Online-Ressource
    Rapid Identification of Clinical Relevant Minor Histocompatibility Antigens via Genome-Wide Zygosity-Genotype Correlation Analysis
    American Association for Cancer Research (AACR) ; 2009
    In:  Clinical Cancer Research Vol. 15, No. 23 ( 2009-12-01), p. 7137-7143
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 23 ( 2009-12-01), p. 7137-7143
    Kurzfassung: Purpose: Identification of minor histocompatibility antigens (mHag) with classic methods often requires sophisticated technologies, determination, and patience. We here describe and validate a nonlaborious and convenient genetic approach, based on genome-wide correlations of mHag zygosities with HapMap single-nucleotide polymorphism genotypes, to identify clinical relevant mHags within a reasonable time frame. Experimental Design: Using this approach, we sought for the mHag recognized by a HLA-DRB1*1501–restricted T-cell clone, isolated from a multiple myeloma patient during a strong graft-versus-tumor effect associated with acute graft-versus-host disease grade 3. Results: In a period of 3 months, we determined the mHag phenotype of 54 HapMap individuals, deduced the zygosity of 20 individuals, defined the mHag locus by zygosity-genotype correlation analyses, tested the putative mHag peptides from this locus, and finally showed that the mHag is encoded by the arginine (R) allele of a nonsynonymous single-nucleotide polymorphism in the SLC19A1 gene. Conclusions: We conclude that this powerful and convenient strategy offers a broadly accessible platform toward rapid identification of mHags associated with graft-versus-tumor effect and graft-versus-host disease. (Clin Cancer Res 2009;15(23):7137–43)
    Materialart: Online-Ressource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-09-1914
    RVK:
    XA 36791
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2009
    ZDB Id: 1225457-5
    ZDB Id: 2036787-9
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
    Online-Ressource
    Online-Ressource
    Targeting of adenovirus to human renal cell carcinoma cells
    Elsevier BV ; 2003
    In:  Urology Vol. 62, No. 3 ( 2003-09), p. 559-565
    Details
    In: Urology, Elsevier BV, Vol. 62, No. 3 ( 2003-09), p. 559-565
    Materialart: Online-Ressource
    ISSN: 0090-4295
    URL: Article
    DOI: 10.1016/S0090-4295(03)00378-9
    Sprache: Englisch
    Verlag: Elsevier BV
    Publikationsdatum: 2003
    ZDB Id: 2011025-X
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
    Online-Ressource
    Online-Ressource
    Rebuilding Human Leukocyte Antigen Class II–Restricted Minor Histocompatibility Antigen Specificity in Recall Antigen-Specific T Cells by Adoptive T Cell Receptor Transfer: Implications for Adoptive Immunotherapy
    American Association for Cancer Research (AACR) ; 2007
    In:  Clinical Cancer Research Vol. 13, No. 13 ( 2007-07-01), p. 4009-4015
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 13, No. 13 ( 2007-07-01), p. 4009-4015
    Kurzfassung: Purpose: Donor T cells directed to hematopoietic minor histocompatibility antigens (mHag) are appealing tools for adoptive immunotherapy of hematological malignancies after allogeneic stem cell transplantation (allo-SCT). Toward the development of a convenient strategy for ex vivo generation of human leukocyte antigen (HLA) class II–restricted mHag-specific T cells, we evaluated the feasibility of rebuilding mHag-specific T cell functions in donor-derived recall antigen-specific T cells via T cell receptor (TCR) transfer. Experimental Design: TCR α- and β-chains of an HLA-DPB1*0401–restricted T-cell clone recognizing a multiple myeloma-associated mHag were retrovirally transferred into a tetanus toxoid (TT)–specific clone derived from the original stem cell donor. TCR double-transduced cells were compared with the parent mHag- and TT-specific clones for antigen specificity, cytokine secretion, and cytotoxic activity and were analyzed for their in vitro expansion capacity in a TT- or mHag-specific fashion. Results: mHag-TCR–transduced TT-specific cells displayed both TT and mHag specificity. Similar to the parent cells, they secreted Th-1 cytokines and exerted significant cytotoxic activity against TT-pulsed or mHag+ target cells, including multiple myeloma cells. A 4-week expansion of TCR-transduced cells via the TT-specific TCR had no negative influence on the mHag-specific cytotoxic activity and resulted in 10- to 100-fold better cell yields as compared with mHag-specific expansion. Conclusions: HLA class II–restricted, mHag-specific effector functions can be successfully reconstructed in donor-derived TT-specific T cells via TCR transfer. Effective expansion of these T cells via TT-specific TCRs illustrate the suitability of this strategy for ex vivo expansion and possibly for in vivo TT-specific reboosting of HLA class II–restricted immunotherapeutic T cells.
    Materialart: Online-Ressource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-07-0286
    RVK:
    XA 36791
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2007
    ZDB Id: 1225457-5
    ZDB Id: 2036787-9
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 8
    Online-Ressource
    Online-Ressource
    Toward targeting B cell cancers with CD4+ CTLs: identification of a CD19-encoded minor histocompatibility antigen using a novel genome-wide analysis
    Rockefeller University Press ; 2008
    In:  The Journal of Experimental Medicine Vol. 205, No. 12 ( 2008-11-24), p. 2863-2872
    Details
    In: The Journal of Experimental Medicine, Rockefeller University Press, Vol. 205, No. 12 ( 2008-11-24), p. 2863-2872
    Kurzfassung: Some minor histocompatibility antigens (mHags) are expressed exclusively on patient hematopoietic and malignant cells, and this unique set of antigens enables specific targeting of hematological malignancies after human histocompatability leucocyte antigen (HLA)–matched allogeneic stem cell transplantation (allo-SCT). We report the first hematopoietic mHag presented by HLA class II (HLA-DQA1*05/B1*02) molecules to CD4+ T cells. This antigen is encoded by a single-nucleotide polymorphism (SNP) in the B cell lineage-specific CD19 gene, which is an important target antigen for immunotherapy of most B cell malignancies. The CD19L-encoded antigen was identified using a novel and powerful genetic strategy in which zygosity-genotype correlation scanning was used as the key step for fine mapping the genetic locus defined by pairwise linkage analysis. This strategy was also applicable for genome-wide identification of a wide range of mHags. CD19L-specific CD4+ T cells provided antigen-specific help for maturation of dendritic cells and for expansion of CD8+ mHag-specific T cells. They also lysed CD19L-positive malignant cells, illustrating the potential therapeutic advantages of targeting this novel CD19L-derived HLA class II–restricted mHag. The currently available immunotherapy strategies enable the exploitation of these therapeutic effects within and beyond allo-SCT settings.
    Materialart: Online-Ressource
    ISSN: 1540-9538 , 0022-1007
    URL: Article
    DOI: 10.1084/jem.20080713
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Rockefeller University Press
    Publikationsdatum: 2008
    ZDB Id: 1477240-1
    Standort Signatur Einschränkungen Verfügbarkeit
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