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Article ; Online: Antibody-epitope conjugates deliver immunogenic T-cell epitopes more efficiently when close to cell surfaces.

van der Wulp, W / Luu, W / Ressing, M E / Schuurman, J / van Kasteren, S I / Guelen, L / Hoeben, R C / Bleijlevens, B / Heemskerk, M H M

mAbs

2024 Volume 16, Issue 1, Page(s) 2329321

Abstract: Antibody-mediated delivery of immunogenic viral ... ...

Abstract	Antibody-mediated delivery of immunogenic viral CD8
MeSH term(s)	Humans ; Epitopes, T-Lymphocyte ; CD8-Positive T-Lymphocytes ; Immunoconjugates ; Antibodies ; Neoplasms/therapy
Chemical Substances	Epitopes, T-Lymphocyte ; Immunoconjugates ; Antibodies
Language	English
Publishing date	2024-03-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2537838-7
ISSN	1942-0870 ; 1942-0870
ISSN (online)	1942-0870
ISSN	1942-0870
DOI	10.1080/19420862.2024.2329321
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Article ; Online: T-cell receptor gene transfer for treatment of leukemia.

Heemskerk, M H M / Griffioen, M / Falkenburg, J H F

Cytotherapy

2008 Volume 10, Issue 2, Page(s) 108–115

Abstract: The therapeutic efficacy of donor lymphocyte infusions has been proven for patients with relapsed hematologic malignancies after allogeneic stem cell transplantation. The beneficial effect of donor lymphocytes, however, is often accompanied by graft- ... ...

Abstract	The therapeutic efficacy of donor lymphocyte infusions has been proven for patients with relapsed hematologic malignancies after allogeneic stem cell transplantation. The beneficial effect of donor lymphocytes, however, is often accompanied by graft-versus-host-disease (GvHD). Adoptive transfer of antigen (Ag)-specific T-cell lines may eradicate the relapsed hematological malignancy, and may separate the anti-leukemic effect from GvHD. The main drawback of adoptive therapy of defined T-cell populations is the difficulty in producing sufficient quantities of these Ag-specific T cells. In addition, the specificity of the infused T cells is difficult to control. As the T-cell receptor (TCR) solely determines the specificity of T cells, transfer of relevant TCR genes into appropriate T-cell populations may provide a potent therapeutic reagent. With this strategy, donor-derived T-cell populations would be equipped with a TCR of defined specificity in short-term in vitro procedures, and infusion of the redirected cells would result in T-cell reactivity against the defined Ag. In this review we discuss the current status of TCR gene transfer for the treatment of hematological malignancies.
MeSH term(s)	Antigens, Neoplasm ; Genetic Therapy/adverse effects ; Humans ; Immunotherapy, Adoptive ; Leukemia/genetics ; Leukemia/therapy ; Lymphoma/genetics ; Lymphoma/therapy ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Antigen, T-Cell/therapeutic use
Chemical Substances	Antigens, Neoplasm ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2008
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2039821-9
ISSN	1477-2566 ; 1465-3249
ISSN (online)	1477-2566
ISSN	1465-3249
DOI	10.1080/14653240701883087
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Article ; Online: T helper 2 response in allergic bronchopulmonary aspergillosis is not driven by specific Aspergillus antigens.

Jolink, H / de Boer, R / Willems, L N A / van Dissel, J T / Falkenburg, J H F / Heemskerk, M H M

Allergy

2015 Volume 70, Issue 10, Page(s) 1336–1339

Abstract: Allergic bronchopulmonary aspergillosis (ABPA) is characterized by an allergic immunological response to Aspergillus fumigatus. In this study, we investigated whether certain Aspergillus antigens are more allergenic than others, as was postulated ... ...

Abstract	Allergic bronchopulmonary aspergillosis (ABPA) is characterized by an allergic immunological response to Aspergillus fumigatus. In this study, we investigated whether certain Aspergillus antigens are more allergenic than others, as was postulated previously. We stimulated peripheral blood mononuclear cells from patients with ABPA with the classically described A. fumigatus allergens Aspf1, Aspf2, Aspf3, and Aspf4, as well as two other Aspergillus antigens, Crf1 and Catalase1. Activated CD4+ T cells displayed a T helper 2 phenotype with the production of IL-4 in response to stimulation with several of these different antigens. Immune responses were not limited to the classically described A. fumigatus allergens. In healthy individuals, we demonstrated a similar recognition profile to the different antigens, but in contrast the activated CD4+ T cells exerted a T helper 1 phenotype and mainly produced IFN-γ after stimulation with A. fumigatus antigens. In conclusion, irrespective of the A. fumigatus antigen, the T-cell immune response in patients with ABPA is skewed to a T helper 2 cytokine secretion profile.
MeSH term(s)	Allergens/immunology ; Antigens, Fungal/immunology ; Aspergillosis, Allergic Bronchopulmonary/immunology ; Cytokines/metabolism ; Humans ; Lymphocyte Activation/immunology ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; Th2 Cells/immunology ; Th2 Cells/microbiology
Chemical Substances	Allergens ; Antigens, Fungal ; Cytokines
Language	English
Publishing date	2015-10
Publishing country	Denmark
Document type	Journal Article
ZDB-ID	391933-x
ISSN	1398-9995 ; 0105-4538
ISSN (online)	1398-9995
ISSN	0105-4538
DOI	10.1111/all.12688
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Article ; Online: Multi-cistronic vector encoding optimized safety switch for adoptive therapy with T-cell receptor-modified T cells.

van Loenen, M M / de Boer, R / Hagedoorn, R S / Jankipersadsing, V / Amir, A L / Falkenburg, J H F / Heemskerk, M H M

Gene therapy

2013 Volume 20, Issue 8, Page(s) 861–867

Abstract: T-cell receptor (TCR) gene transfer is an attractive strategy to equip T cells with defined antigen-specific TCRs using short-term in vitro procedures to target both hematological malignancies and solid tumors. TCR gene transfer poses different safety ... ...

Abstract	T-cell receptor (TCR) gene transfer is an attractive strategy to equip T cells with defined antigen-specific TCRs using short-term in vitro procedures to target both hematological malignancies and solid tumors. TCR gene transfer poses different safety issues that might warrant the inclusion of a suicide gene. High affinity TCRs may result in on-target toxicity, and off-target reactivity directed against healthy tissue can be observed due to mixed TCR dimers. Inclusion of a suicide gene as a safety switch may abrogate these unwanted toxicities. Human CD20 has been proposed as a nonimmunogenic suicide gene targeted by widely used clinical-grade anti-CD20 antibodies that can additionally function as a selection marker. However, transduction of T cells with a multi-cistronic vector encoding both TCR and CD20 resulted in poor coexpression. In this study, we demonstrated that codon optimization of TCR and CD20 resulted in profound coexpression of both the preferentially expressed antigen in melanoma (PRAME)-TCR and CD20, allowing selective as well as efficient elimination of these engineered T cells in vitro. These results demonstrate the great potential of codon optimized CD20 to be broadly used in clinical trials as a safety switch.
MeSH term(s)	Antibodies, Monoclonal/genetics ; Antigens, CD20/genetics ; Antigens, CD20/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cell Line, Tumor ; Gene Transfer Techniques ; Genes/genetics ; Genes, Transgenic, Suicide ; Genetic Vectors ; Humans ; Immunotherapy, Adoptive ; Melanoma/genetics ; Melanoma/immunology ; Melanoma/therapy ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/immunology ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
Chemical Substances	Antibodies, Monoclonal ; Antigens, CD20 ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2013-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1191036-7
ISSN	1476-5462 ; 0969-7128
ISSN (online)	1476-5462
ISSN	0969-7128
DOI	10.1038/gt.2013.4
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Article ; Online: Cognate CD4 T-cell licensing of dendritic cells heralds anti-cytomegalovirus CD8 T-cell immunity after human allogeneic umbilical cord blood transplantation.

Flinsenberg, T W H / Spel, L / Jansen, M / Koning, D / de Haar, C / Plantinga, M / Scholman, R / van Loenen, M M / Nierkens, S / Boon, L / van Baarle, D / Heemskerk, M H M / Boelens, J J / Boes, M

Journal of virology

2015 Volume 89, Issue 2, Page(s) 1058–1069

Abstract: Unlabelled: Reactivation of human cytomegalovirus (CMV) is hazardous to patients undergoing allogeneic cord blood transplantation (CBT), lowering survival rates by approximately 25%. While antiviral treatment ameliorates viremia, complete viral control ... ...

Abstract	Unlabelled: Reactivation of human cytomegalovirus (CMV) is hazardous to patients undergoing allogeneic cord blood transplantation (CBT), lowering survival rates by approximately 25%. While antiviral treatment ameliorates viremia, complete viral control requires CD8+ T-cell-driven immunity. Mouse studies suggest that cognate antigen-specific CD4+ T-cell licensing of dendritic cells (DCs) is required to generate effective CD8+ T-cell responses. For humans, this was not fully understood. We here show that CD4+ T cells are essential for licensing of human DCs to generate effector and memory CD8+ T-cell immunity against CMV in CBT patients. First, we show in CBT recipients that clonal expansion of CMV-pp65-specific CD4+ T cells precedes the rise in CMV-pp65-specific CD8+ T cells. Second, the elicitation of CMV-pp65-specific CD8+ T cells from rare naive precursors in cord blood requires DC licensing by cognate CMV-pp65-specific CD4+ T cells. Finally, also CD8+ T-cell memory responses require CD4+ T-cell-mediated licensing of DCs in our system, by secretion of gamma interferon (IFN-γ) by pp65-specific CD4+ T cells. Together, these data show that human DCs require licensing by cognate antigen-specific CD4+ T cells to elicit effective CD8+ T-cell-mediated immunity and fight off viral reactivation in CBT patients. Importance: Survival rates after stem cell transplantation are lowered by 25% when patients undergo reactivation of cytomegalovirus (CMV) that they harbor. Immune protection against CMV is mostly executed by white blood cells called killer T cells. We here show that for generation of optimally protective killer T-cell responses that respond to CMV, the early elicitation of help from a second branch of CMV-directed T cells, called helper T cells, is required.
MeSH term(s)	Adolescent ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Child ; Child, Preschool ; Cord Blood Stem Cell Transplantation ; Cytomegalovirus/immunology ; Cytomegalovirus/physiology ; Dendritic Cells/immunology ; Female ; Humans ; Infant ; Infant, Newborn ; Interferon-gamma/secretion ; Male ; Phosphoproteins/immunology ; Viral Matrix Proteins/immunology ; Virus Activation
Chemical Substances	Phosphoproteins ; Viral Matrix Proteins ; cytomegalovirus matrix protein 65kDa ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2015-01-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01850-14
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Article: Minor histocompatibility antigens as targets of graft-versus-leukemia reactions.

Falkenburg, J H F / Marijt, W A F / Heemskerk, M H M / Willemze, R

Current opinion in hematology

2002 Volume 9, Issue 6, Page(s) 497–502

Abstract: The main advantage of allogeneic stem cell transplantation over autologous stem cell transplantation for hematologic malignancies is the ability to perform cellular immunotherapy using donor-derived immune effector cells after transplantation. In HLA- ... ...

Abstract	The main advantage of allogeneic stem cell transplantation over autologous stem cell transplantation for hematologic malignancies is the ability to perform cellular immunotherapy using donor-derived immune effector cells after transplantation. In HLA-matched allogeneic stem cell transplantation, the beneficial graft-versus-leukemia effect of donor lymphocytes appears to be caused mainly by alloreactive T cells that are capable of recognizing minor histocompatibility antigens on the malignant cell population from the patient. The tissue distribution of minor histocompatibility antigens probably determines the clinical result of T-cell responses against these antigens. Whereas T cells recognizing broadly expressed antigens cause not only graft-versus-leukemia but also graft-versus-host disease, T cells recognizing minor histocompatibility antigens specifically expressed on hematopoietic cells may mainly eliminate hematopoietic cells from the recipient, including the malignant cells, without affecting donor hematopoiesis or normal nonhematopoietic tissues. Graft-versus-host disease may still occur because of the induction of inflammatory responses against hematopoietic cells in the tissues. Vaccination of patients after transplantation or vaccination of stem cell donors before transplantation using minor histocompatibility antigen-specific peptides, production of minor histocompatibility antigen-specific T cells, and redirection of T-cell specificity by gene transfer of T-cell receptors may be strategies to eradicate specifically the malignant cells after allogeneic stem cell transplantation.
MeSH term(s)	Antigens, Neoplasm/immunology ; Antigens, Neoplasm/therapeutic use ; Graft vs Leukemia Effect/immunology ; Hematologic Neoplasms/therapy ; Hematopoietic Stem Cell Transplantation/methods ; Humans ; Immunotherapy, Adoptive/methods ; Lymphocyte Transfusion ; Minor Histocompatibility Antigens/immunology ; Minor Histocompatibility Antigens/therapeutic use ; Transplantation, Homologous/immunology ; Transplantation, Homologous/methods
Chemical Substances	Antigens, Neoplasm ; Minor Histocompatibility Antigens
Language	English
Publishing date	2002-10-22
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1153887-9
ISSN	1531-7048 ; 1065-6251
ISSN (online)	1531-7048
ISSN	1065-6251
DOI	10.1097/00062752-200211000-00005
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Article ; Online: In vitro generation of mature, naive antigen-specific CD8(+) T cells with a single T-cell receptor by agonist selection.

Snauwaert, S / Verstichel, G / Bonte, S / Goetgeluk, G / Vanhee, S / Van Caeneghem, Y / De Mulder, K / Heirman, C / Stauss, H / Heemskerk, M H M / Taghon, T / Leclercq, G / Plum, J / Langerak, A W / Thielemans, K / Kerre, T / Vandekerckhove, B

Leukemia

2013 Volume 28, Issue 4, Page(s) 830–841

Abstract: Peripheral blood T cells transduced with a tumor-specific T-cell receptor (TCR) face problems of auto-reactivity and lack of efficacy caused by cross-pairing of exogenous and endogenous TCR chains, as well as short term in vivo survival due to activation ...

Abstract	Peripheral blood T cells transduced with a tumor-specific T-cell receptor (TCR) face problems of auto-reactivity and lack of efficacy caused by cross-pairing of exogenous and endogenous TCR chains, as well as short term in vivo survival due to activation and growth factor-induced differentiation. We here studied an alternative strategy for the efficient generation of naive CD8(+) T cells with a single TCR. TCR-transduced human postnatal thymus-derived and adult mobilized blood-derived hematopoietic progenitor cells (HPCs) were differentiated to CD4(+)CD8(+) double-positive T cells using OP9-Delta-like 1 (OP9-DL1) cultures. Addition of the agonist peptide induced double positive cells to cross-present the peptide, leading, in the absence of co-stimulation, to cell cycle arrest and differentiation into mature CD8(+) T cells. Comprehensive phenotypic, molecular and functional analysis revealed the generation of naive and resting CD8(+) T cells through a process similar to thymic positive selection. These mature T cells show a near complete inhibition of endogenous TCRA and TCRB rearrangements and express high levels of the introduced multimer-reactive TCR. Upon activation, specific cytokine production and efficient killing of tumor cells were induced. Using this strategy, large numbers of high-avidity tumor-specific naive T cells can be generated from readily available HPCs without TCR chain cross-pairing.
MeSH term(s)	Adult ; CD8-Positive T-Lymphocytes/immunology ; Cell Differentiation ; Cell Line, Tumor ; Child ; Child, Preschool ; Gene Rearrangement, T-Lymphocyte ; Humans ; Immunotherapy, Adoptive ; Infant ; Infant, Newborn ; Receptors, Antigen, T-Cell/agonists ; Receptors, Antigen, T-Cell/physiology
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2013-10-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/leu.2013.285
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Article: HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity.

van der Veken, L T / Hoogeboom, M / de Paus, R A / Willemze, R / Falkenburg, J H F / Heemskerk, M H M

Gene therapy

2005 Volume 12, Issue 23, Page(s) 1686–1695

Abstract: Both cytotoxic T cells and helper T cells are important in immune responses against pathogens and malignant cells. In hematological malignancies which express HLA class II molecules, immunotherapy may be directed to HLA class II restricted antigens. We ... ...

Abstract	Both cytotoxic T cells and helper T cells are important in immune responses against pathogens and malignant cells. In hematological malignancies which express HLA class II molecules, immunotherapy may be directed to HLA class II restricted antigens. We investigated whether it is possible to engineer HLA class II restricted T cells with both antigen-specific cytolytic activity and the capacity to produce high amounts of cytokines. CD4+ and CD8+ peripheral-blood-derived T cells were retrovirally transduced with the HLA class II restricted minor histocompatibility antigen dead box RNA helicase Y (DBY)-specific TCR. The TCR-transduced CD4+ T cells exerted DBY-specific cytolytic activity, produced Th0, Th1, or Th2 cytokines, and proliferated upon DBY-specific stimulation. TCR-transduced CD8+ T cells exerted cytolytic activity which equaled the level of cytolytic activity of the TCR-transferred CD4+ T cells. Cotransfer of CD4 enhanced the cytolytic activity of the TCR-transduced CD8+ T cells, but introduction of CD4 was not sufficient to generate DBY-specific CD8+ T cells with the capacity to produce high amounts of cytokines. In this study, we demonstrated the feasibility to engineer T cells with antigen-specific cytolytic activity, as well as the ability to produce significant amounts of cytokines, by TCR transfer to CD4+ T cells.
MeSH term(s)	Cells, Cultured ; Clone Cells ; DNA Primers ; Genes, MHC Class II ; Genetic Engineering ; Genetic Therapy/methods ; Genetic Vectors/administration & dosage ; Genetic Vectors/genetics ; Hematologic Neoplasms/immunology ; Hematologic Neoplasms/therapy ; Humans ; Immunotherapy/methods ; Male ; Receptors, Antigen, T-Cell/genetics ; Retroviridae/genetics ; T-Lymphocytes/immunology ; T-Lymphocytes, Cytotoxic/immunology ; T-Lymphocytes, Helper-Inducer/immunology ; Transduction, Genetic/methods
Chemical Substances	DNA Primers ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2005-12
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1191036-7
ISSN	1476-5462 ; 0969-7128
ISSN (online)	1476-5462
ISSN	0969-7128
DOI	10.1038/sj.gt.3302586
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Article ; Online: The human leukocyte antigen-presented ligandome of B lymphocytes

Hassan, C. / Kester, M.G.D. / Ru, A.H. / Hombrink, P. / Drijfhout, J.W. / Nijveen, H. / Leunissen, J.A.M. / Heemskerk, M.H.M. / Falkenburg, J.H.F. / van Veelen, P.A.

Molecular and Cellular Proteomics

2013 Volume 12

Abstract: Peptides presented by human leukocyte antigen (HLA) molecules on the cell surface play a crucial role in adaptive immunology, mediating the communication between T cells and antigen presenting cells. Knowledge of these peptides is of pivotal importance ... ...

Abstract	Peptides presented by human leukocyte antigen (HLA) molecules on the cell surface play a crucial role in adaptive immunology, mediating the communication between T cells and antigen presenting cells. Knowledge of these peptides is of pivotal importance in fundamental studies on T cell action, and in cellular immunotherapy and transplantation. In this study we present the in-depth identification and relative quantification of 14,500 peptide ligands constituting the HLA-ligandome of B-cells. This large number of identified ligands provides a general insight in the presented peptide repertoire and antigen presentation. Our uniquely large set of HLA-ligands allowed us to characterize in detail the peptides constituting the ligandome in terms of relative abundance, peptide length distribution, physicochemical properties, binding affinity to the HLA molecule and presence of post-translational modifications. The presented B-lymphocyte ligandome is shown to be a rich source of information by the presence of minor histocompatibility antigens, virus-derived epitopes and post-translationally modified HLA ligands and can be a good starting point to solve a wealth of specific immunological questions. These HLA ligands can form the basis for reversed immunology approaches to identify T cell epitopes, not based on in silico predictions, but based on the bona fide eluted HLA-ligandome.
Keywords	cancer-cells ; complex ; epitopes ; hla class-i ; identification ; mass-spectrometry ; minor histocompatibility antigen ; peptide motifs ; t-cell responses ; versus-host-disease
Subject code	570
Language	English
Publishing country	nl
Document type	Article ; Online
ZDB-ID	2075924-1
ISSN	1535-9484 ; 1535-9476
ISSN (online)	1535-9484
ISSN	1535-9476
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Article ; Online: Discovery of T cell epitopes implementing HLA-peptidomics into a reverse immunology approach

Hombrink, P. / Hassan, C. / Kester, M.G.D. / Ru, A.H. / Bergen, C.A.M. / Nijveen, H. / Drijfhout, J.W. / Falkenburg, J.H.F. / Heemskerk, M.H.M. / van Veelen, P.A.

The Journal of Immunology

2013 Volume 190, Issue 8

Abstract: T cell recognition of minor histocompatibility Ags (MiHA) plays an important role in the graft-versus-tumor effect of allogeneic stem cell transplantation. Selective infusion of T cells reactive for hematopoiesis-restricted MiHA presented in the context ... ...

Abstract	T cell recognition of minor histocompatibility Ags (MiHA) plays an important role in the graft-versus-tumor effect of allogeneic stem cell transplantation. Selective infusion of T cells reactive for hematopoiesis-restricted MiHA presented in the context of HLA class I or II molecules may help to separate the graft-versus-tumor effects from graft-versus-host disease effects after allogeneic stem cell transplantation. Over the years, increasing numbers of MiHA have been identified by forward immunology approaches, and the relevance of these MiHA has been illustrated by correlation with clinical outcome. As the tissue distribution of MiHA affects the clinical outcome of T cell responses against these Ags, it would be beneficial to identify additional predefined MiHA that are exclusively expressed on hematopoietic cells. Therefore, several reverse immunology approaches have been explored for the prediction of MiHA. Thus far, these approaches frequently resulted in the identification of T cells directed against epitopes that are not naturally processed and presented. In this study we established a method for the identification of biologically relevant MiHA, implementing mass spectrometry–based HLA-peptidomics into a reverse immunology approach. For this purpose, HLA class I binding peptides were eluted from transformed B cells, analyzed by mass spectrometry, and matched with a database dedicated to identifying polymorphic peptides. This process resulted in a set of 40 MiHA candidates that were evaluated in multiple selection steps. The identification of LB-NISCH-1A demonstrated the technical feasibility of our approach. On the basis of these results, we present an approach that can be of value for the efficient identification of MiHA or other T cell epitopes.
Keywords	complexes ; gene ; identification ; immunotherapy ; leukemia ; lymphocytes ; minor histocompatibility antigens ; peptides ; restricted tissue distribution ; versus-host-disease
Subject code	610
Language	English
Publishing country	nl
Document type	Article ; Online
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
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