Tanja Gruijl - Academia.edu (original) (raw)

Papers by Tanja Gruijl

Research paper thumbnail of Selectively hampered activation of lymph node-resident dendritic cells precedes profound T cell suppression and metastatic spread in the breast cancer sentinel lymph node

Journal for ImmunoTherapy of Cancer, 2019

Background: Immune regulated pathways influence both breast cancer (BrC) development and response... more Background: Immune regulated pathways influence both breast cancer (BrC) development and response to (neo) adjuvant chemotherapy. The sentinel lymph node (SLN), as the first metastatic site, is also the first site where BrCinduced suppression of immune effector subsets occurs. Since intricate knowledge of the phenotypic and functional status of these immune effector subsets is lacking, we set out to map the immune landscape of BrC SLN. Methods: Viable LN cells from BrC SLN (n = 58) were used for detailed flowcytometry-assisted mapping of the immune landscape of BrC SLN in a comparative analysis with healthy (i.e. prophylactic mastectomy-derived) axillary lymph nodes (HLN, n = 17). Findings were related to clinicopathological characteristics. Results: Our data show that BrC-induced immune suppression in tumor-involved SLN, as evidenced by increased Treg and MDSC rates as well as by a generalized state of T cell anergy, coincides with hampered activation of LN-resident (LNR) dendritic cell (DC) subsets rather than of migratory DC subsets. Importantly, suppression of these LN-resident DC subsets preceded profoundly disabled T cell effector functions in tumor-involved SLN. Furthermore, we provide evidence that the suppressed state of LNR-cDC is not only related to nodal involvement but is also related to high-risk breast cancer subtypes that lack expression of hormone receptors and may be a negative predictor of disease-free survival. Conclusion: These data thus provide new insights in the mechanisms underlying loco-regional immune suppression induced by BrC and how these relate to clinical outcome. They identify the LNR-cDC subset as a pivotal regulatory node in cellular immune suppressive pathways and therefore as a promising therapeutic target to combat immune suppression and secure the induction of effective antitumor immunity, e.g. in combination with neo-adjuvant chemotherapy.

Research paper thumbnail of Additional file 3: of Stereotactic ablative radiotherapy for the comprehensive treatment of 4â 10 oligometastatic tumors (SABR-COMET-10): study protocol for a randomized phase III trial

Sample Consent Form. Sample Consent Form. (DOC 129 kb)

Research paper thumbnail of Additional file 2: of Stereotactic ablative radiotherapy for the comprehensive treatment of 4â 10 oligometastatic tumors (SABR-COMET-10): study protocol for a randomized phase III trial

World Health Organization Trial Registration Dataset. List of Fields in Trial Registration Databa... more World Health Organization Trial Registration Dataset. List of Fields in Trial Registration Database. (DOC 76 kb)

Research paper thumbnail of Lymphoid and myeloid biomarkers for clinical outcome of combined immunotherapy with granulocyte-macrophage colony-stimulating factor-tranduced allogeneic prostate cancer cells (GVAX) and ipilimumab in castration-resistant prostate cancer patients

Journal of Clinical Oncology, 2012

2562 Background: In a phase-I dose escalation trial in patients with castration-resistant prostat... more 2562 Background: In a phase-I dose escalation trial in patients with castration-resistant prostate cancer we showed that GVAX and ipilimumab had an acceptable safety profile. Moreover, we observed tumor responses and prolonged survival as compared to the Halabi predicted overall survival (OS). However, ipilimumab can also lead to severe immune-related adverse events. To avoid unnecessary exposure to this risk, it is essential to identify biomarkers that correlate with clinical activity. Methods: Patients had castration-resistant prostate cancer and were chemotherapy-naïve. They received bi-weekly GVAX for a 24 week period combined with monthly intravenous administrations of ipilimumab. Each cohort of 3 patients received an escalating dose of ipilimumab at 0·3, 1·0, 3·0 or 5·0 mg/kg. In an expansion cohort 16 patients were treated with GVAX and 3·0 mg/kg ipilimumab. Flowcytometric monitoring of lymphoid and myeloid subsets in blood were performed. Results: We observed a significantly...

Research paper thumbnail of Cancer vaccine strategies get bigger and better

Research paper thumbnail of Dendritic cells: A novel therapeutic modality

Research paper thumbnail of Highly specific and potently activating Vγ9Vδ2-T cell specific nanobodies for diagnostic and therapeutic applications

Clinical Immunology, 2016

Vγ9Vδ2-T cells constitute the predominant subset of γδ-T cells in human peripheral blood and have... more Vγ9Vδ2-T cells constitute the predominant subset of γδ-T cells in human peripheral blood and have been shown to play an important role in antimicrobial and antitumor immune responses. Several efforts have been initiated to exploit these cells for cancer immunotherapy, e.g. by using phosphoantigens, adoptive cell transfer, and by a bispecific monoclonal antibody based approach. Here, we report the generation of a novel set of Vγ9Vδ2-T cell specific VHH (or nanobody). VHH have several advantages compared to conventional antibodies related to their small size, stability, ease of generating multispecific molecules and low immunogenicity. With high specificity and affinity, the anti-Vγ9Vδ2-T cell receptor VHHs are shown to be useful for FACS, MACS and immunocytochemistry. In addition, some VHH were found to specifically activate Vγ9Vδ2-T cells. Besides being of possible immunotherapeutic value, these single domain antibodies will be of great value in the further study of this important immune effector cell subset.

Research paper thumbnail of Generation and characterization of CD1d-specific single-domain antibodies with distinct functional features

Immunology, 2016

Ligation of the CD1d antigen-presenting molecule by monoclonal antibodies (mAbs) can trigger impo... more Ligation of the CD1d antigen-presenting molecule by monoclonal antibodies (mAbs) can trigger important biological functions. For therapeutic purposes camelid-derived variable domain of heavy-chain-only antibodies (VHH) have multiple advantages over mAbs because they are small, stable and have low immunogenicity. Here, we generated 21 human CD1d-specific VHH by immunizing Lama glama and subsequent phage display. Two clones induced maturation of dendritic cells, one clone induced early apoptosis in CD1d-expressing B lymphoblasts and multiple myeloma cells, and another clone blocked recognition of glycolipid-loaded CD1d by CD1d-restricted invariant natural killer T (iNKT) cells. In contrast to reported CD1d-specific mAbs, these CD1d-specific VHH have the unique characteristic that they induce specific and well-defined biological effects. This feature, combined with the above-indicated general advantages of VHH, make the CD1d-specific VHH generated here unique and useful tools to exploit both CD1d ligation as well as disruption of CD1d-iNKT interactions in the treatment of cancer or inflammatory disorders.

Research paper thumbnail of Adjuvant treatment of early-stage melanoma by local i.d. administration of low-dose CpG-B and GM-CSF increases recurrence-free survival: long-term follow-up of three randomized clinical trials

Journal for ImmunoTherapy of Cancer, 2015

Research paper thumbnail of S48. Biomarker development for ipilimumab and prostate GVAX treatment

Journal for ImmunoTherapy of Cancer, 2014

Research paper thumbnail of An α-galactosylceramide nose job shapes up iNKT cells

Research paper thumbnail of Bulldozing β-linked glycolipids for recognition by invariant NKT cells

Research paper thumbnail of Gram-positive bacteria: a major microbial ‘turn-on’ for invariant NKT cells

Immunotherapy, 2012

Invariant NKT (iNKT) cells are evolution‐ arily conserved immunoregulatory cells that are charact... more Invariant NKT (iNKT) cells are evolution‐ arily conserved immunoregulatory cells that are characterized by an extremely restricted T‐cell antigen receptor (TCR) repertoire (Va14–Ja18 in mice and Va24–Ja18 in humans) and that can be activated by glyco‐ lipid antigen presented in the context of the nonpolymorphic MHC class I‐like molecule CD1d [1]. It is well known that iNKT cells can participate in antimicrobial immune responses. In some cases, this results from activation of iNKT by inflammatory cyto‐ kines and/or self‐antigen presented by CD1d; in other cases (e.g., infection with Sphingomonas species and Borrelia burgdorferi), this directly results from the pre‐ sentation of microbial glycolipids by CD1d to iNKT [1]. As in general neither of these microbes causes lethal diseases, it is still a matter of debate what exactly is the driv‐ ing evolutionary force behind the strongly c onserved iNKT–CD1d recognition system. In a recent paper in Nature Immunology, Kinjo et al. provide compelling evidence that iNKT cells directly recognize glycolipid antigens from highly pathogenic group B Streptococcus and Streptococcus pneumoniae in a CD1d‐restricted and invariant TCR (iTCR)‐dependent fashion [2]. These data are in accordance with an earlier obser‐ vation that infection with S. pneumoniae resulted in increased bacterial growth and reduced survival in iNKT‐deficient com‐ pared with wild‐type mice [3]. Glycolipids of S. pneumoniae and group B Streptococcus were found to be diacylglycerol based and contained a cis‐vaccenic acid that, in order to be an iNKT agonist, was exclusively required to be in the sn‐2 glycerol position. cis‐vaccenic acid, which is uncommon in mammalian cells and therefore considered a microbial structure, was found to bind in the A’ antigen‐binding pocket of CD1d encircling the A’ pole in a clockwise fashion, allowing the remaining fatty acid to bind in the opposite F’ pocket leaving the a‐ano‐ meric glucose exposed for TCR recogni‐ tion. In this way, the unique hydrophobic lipid chains of the S. pneumoniae antigens contribute to the iTCR epitope (and iNKT activation) by defining the positioning of the exposed sugar. This study highlights not only the role of iNKT cells in the immune response against pathogens that are of worldwide clinical significance, and the stringent require‐ ments for both lipid and sugar structures in allowing interactions between CD1d and iNKT, but also suggests that the iTCR may have been evolutionarily conserved owing to its ability to recognize a set of widely dis‐ tributed glycolipids that are considered an essential part of many microbes, including potentially life‐threatening strains.

Research paper thumbnail of Bispecific antibody platforms for cancer immunotherapy

Critical Reviews in Oncology/Hematology, 2014

Over the past decades advances in bioengineering and expanded insight in tumor immunology have re... more Over the past decades advances in bioengineering and expanded insight in tumor immunology have resulted in the emergence of novel bispecific antibody (bsAb) constructs that are capable of redirecting immune effector cells to the tumor microenvironment. (Pre-) clinical studies of various bsAb constructs have shown impressive results in terms of immune effector cell retargeting, target dependent activation and the induction of anti-tumor responses. This review summarizes recent advances in the field of bsAb-therapy and limitations that were encountered. Furthermore, we will discuss potential future developments that can be expected to take the bsAb approach successfully forward.

Research paper thumbnail of Priming of PRAME- and WT1-specific CD8+T cells in healthy donors but not in AML patients in complete remission

OncoImmunology, 2013

Active immunotherapy may prevent the relapse of acute myeloid leukemia (AML) by inducing leukemia... more Active immunotherapy may prevent the relapse of acute myeloid leukemia (AML) by inducing leukemia-specific t cells. Here, we investigated whether Wilms' tumor 1 (Wt1) and preferentially expressed antigen in melanoma (prAMe)-specific t cells could be induced upon the priming of healthy donor-and AML patient-derived t cells with HLA-A2-matched, peptide-loaded allogeneic dendritic cells. AML-reactive, tetramer (tm)-binding and interferon-producing, cytotoxic t lymphocytes specific for prAMe could readily be isolated from healthy individuals and maintained in culture. In this setting, priming efficacy was significantly higher for prAMe than for Wt1. the priming of t cells from patient-derived material proved to be near-to-impossible: No leukemia-associated antigen (LAA)-specific t cell could be primed in 4 patients that had recently achieved a complete response (Cr), and in only 1 out of 3 patients exhibiting a sustained Cr we did observe Wt1-specific t cells, though with a low frequency. these findings suggest that the functionality and/or repertoire of t cells differ in healthy subjects and AML patients in Cr, and may have repercussions for the implementation of active vaccination approaches against AML.

Research paper thumbnail of Functional characterization of a STAT3-dependent dendritic cell-derived CD14+cell population arising upon IL-10-driven maturation

Research paper thumbnail of Specific tumor targeting and activation of Vγ9Vδ2 T cells by bi-specific nanobodies

Journal for ImmunoTherapy of Cancer, 2014

Research paper thumbnail of The effects of pre-operative administration of CpG 7909 on dendritic and T cell subsets in the sentinel lymph node of stage I/II melanoma patients

Research paper thumbnail of Human dendritic cell line models for DC differentiation and clinical DC vaccination studies

Journal of Leukocyte Biology, 2008

Research paper thumbnail of Prolonged Maturation and Enhanced Transduction of Dendritic Cells Migrated from Human Skin Explants After In Situ Delivery of CD40-Targeted Adenoviral Vectors

The Journal of Immunology, 2002

Therapeutic tumor vaccination with viral vectors or naked DNA, carrying the genetic code for tumo... more Therapeutic tumor vaccination with viral vectors or naked DNA, carrying the genetic code for tumor-associated Ags, critically depends on the in vivo transduction of dendritic cells (DC). Transfection of predominantly nonprofessional APC and only small numbers of DC may hamper proper T cell activation. Aim of this study was, therefore, the targeted, selective, and enhanced in situ transduction of DC. A human skin explant model was used to explore targeted transduction of cutaneous DC after intradermal injection of a bispecific Ab conjugate to link adenoviral (Ad) vectors directly to CD40 on the DC surface. A significantly enhanced transduction efficiency and selectivity, and an increased activation state of migrating DC were thus achieved. Moreover, DC transduced by CD40-targeted Ad maintained their Ag-specific CTL-stimulatory ability for up to 1 wk after the start of migration, in contrast to DC transduced by untargeted Ad, which had lost this capacity by that time. Because DC targeting in vivo might obviate the need for the in vitro culture of autologous DC for adoptive transfer, CD40-targeted Ad vectors constitute a promising new vaccine modality for tumor immunotherapy.

Research paper thumbnail of Selectively hampered activation of lymph node-resident dendritic cells precedes profound T cell suppression and metastatic spread in the breast cancer sentinel lymph node

Journal for ImmunoTherapy of Cancer, 2019

Background: Immune regulated pathways influence both breast cancer (BrC) development and response... more Background: Immune regulated pathways influence both breast cancer (BrC) development and response to (neo) adjuvant chemotherapy. The sentinel lymph node (SLN), as the first metastatic site, is also the first site where BrCinduced suppression of immune effector subsets occurs. Since intricate knowledge of the phenotypic and functional status of these immune effector subsets is lacking, we set out to map the immune landscape of BrC SLN. Methods: Viable LN cells from BrC SLN (n = 58) were used for detailed flowcytometry-assisted mapping of the immune landscape of BrC SLN in a comparative analysis with healthy (i.e. prophylactic mastectomy-derived) axillary lymph nodes (HLN, n = 17). Findings were related to clinicopathological characteristics. Results: Our data show that BrC-induced immune suppression in tumor-involved SLN, as evidenced by increased Treg and MDSC rates as well as by a generalized state of T cell anergy, coincides with hampered activation of LN-resident (LNR) dendritic cell (DC) subsets rather than of migratory DC subsets. Importantly, suppression of these LN-resident DC subsets preceded profoundly disabled T cell effector functions in tumor-involved SLN. Furthermore, we provide evidence that the suppressed state of LNR-cDC is not only related to nodal involvement but is also related to high-risk breast cancer subtypes that lack expression of hormone receptors and may be a negative predictor of disease-free survival. Conclusion: These data thus provide new insights in the mechanisms underlying loco-regional immune suppression induced by BrC and how these relate to clinical outcome. They identify the LNR-cDC subset as a pivotal regulatory node in cellular immune suppressive pathways and therefore as a promising therapeutic target to combat immune suppression and secure the induction of effective antitumor immunity, e.g. in combination with neo-adjuvant chemotherapy.

Research paper thumbnail of Additional file 3: of Stereotactic ablative radiotherapy for the comprehensive treatment of 4â 10 oligometastatic tumors (SABR-COMET-10): study protocol for a randomized phase III trial

Sample Consent Form. Sample Consent Form. (DOC 129 kb)

Research paper thumbnail of Additional file 2: of Stereotactic ablative radiotherapy for the comprehensive treatment of 4â 10 oligometastatic tumors (SABR-COMET-10): study protocol for a randomized phase III trial

World Health Organization Trial Registration Dataset. List of Fields in Trial Registration Databa... more World Health Organization Trial Registration Dataset. List of Fields in Trial Registration Database. (DOC 76 kb)

Research paper thumbnail of Lymphoid and myeloid biomarkers for clinical outcome of combined immunotherapy with granulocyte-macrophage colony-stimulating factor-tranduced allogeneic prostate cancer cells (GVAX) and ipilimumab in castration-resistant prostate cancer patients

Journal of Clinical Oncology, 2012

2562 Background: In a phase-I dose escalation trial in patients with castration-resistant prostat... more 2562 Background: In a phase-I dose escalation trial in patients with castration-resistant prostate cancer we showed that GVAX and ipilimumab had an acceptable safety profile. Moreover, we observed tumor responses and prolonged survival as compared to the Halabi predicted overall survival (OS). However, ipilimumab can also lead to severe immune-related adverse events. To avoid unnecessary exposure to this risk, it is essential to identify biomarkers that correlate with clinical activity. Methods: Patients had castration-resistant prostate cancer and were chemotherapy-naïve. They received bi-weekly GVAX for a 24 week period combined with monthly intravenous administrations of ipilimumab. Each cohort of 3 patients received an escalating dose of ipilimumab at 0·3, 1·0, 3·0 or 5·0 mg/kg. In an expansion cohort 16 patients were treated with GVAX and 3·0 mg/kg ipilimumab. Flowcytometric monitoring of lymphoid and myeloid subsets in blood were performed. Results: We observed a significantly...

Research paper thumbnail of Cancer vaccine strategies get bigger and better

Research paper thumbnail of Dendritic cells: A novel therapeutic modality

Research paper thumbnail of Highly specific and potently activating Vγ9Vδ2-T cell specific nanobodies for diagnostic and therapeutic applications

Clinical Immunology, 2016

Vγ9Vδ2-T cells constitute the predominant subset of γδ-T cells in human peripheral blood and have... more Vγ9Vδ2-T cells constitute the predominant subset of γδ-T cells in human peripheral blood and have been shown to play an important role in antimicrobial and antitumor immune responses. Several efforts have been initiated to exploit these cells for cancer immunotherapy, e.g. by using phosphoantigens, adoptive cell transfer, and by a bispecific monoclonal antibody based approach. Here, we report the generation of a novel set of Vγ9Vδ2-T cell specific VHH (or nanobody). VHH have several advantages compared to conventional antibodies related to their small size, stability, ease of generating multispecific molecules and low immunogenicity. With high specificity and affinity, the anti-Vγ9Vδ2-T cell receptor VHHs are shown to be useful for FACS, MACS and immunocytochemistry. In addition, some VHH were found to specifically activate Vγ9Vδ2-T cells. Besides being of possible immunotherapeutic value, these single domain antibodies will be of great value in the further study of this important immune effector cell subset.

Research paper thumbnail of Generation and characterization of CD1d-specific single-domain antibodies with distinct functional features

Immunology, 2016

Ligation of the CD1d antigen-presenting molecule by monoclonal antibodies (mAbs) can trigger impo... more Ligation of the CD1d antigen-presenting molecule by monoclonal antibodies (mAbs) can trigger important biological functions. For therapeutic purposes camelid-derived variable domain of heavy-chain-only antibodies (VHH) have multiple advantages over mAbs because they are small, stable and have low immunogenicity. Here, we generated 21 human CD1d-specific VHH by immunizing Lama glama and subsequent phage display. Two clones induced maturation of dendritic cells, one clone induced early apoptosis in CD1d-expressing B lymphoblasts and multiple myeloma cells, and another clone blocked recognition of glycolipid-loaded CD1d by CD1d-restricted invariant natural killer T (iNKT) cells. In contrast to reported CD1d-specific mAbs, these CD1d-specific VHH have the unique characteristic that they induce specific and well-defined biological effects. This feature, combined with the above-indicated general advantages of VHH, make the CD1d-specific VHH generated here unique and useful tools to exploit both CD1d ligation as well as disruption of CD1d-iNKT interactions in the treatment of cancer or inflammatory disorders.

Research paper thumbnail of Adjuvant treatment of early-stage melanoma by local i.d. administration of low-dose CpG-B and GM-CSF increases recurrence-free survival: long-term follow-up of three randomized clinical trials

Journal for ImmunoTherapy of Cancer, 2015

Research paper thumbnail of S48. Biomarker development for ipilimumab and prostate GVAX treatment

Journal for ImmunoTherapy of Cancer, 2014

Research paper thumbnail of An α-galactosylceramide nose job shapes up iNKT cells

Research paper thumbnail of Bulldozing β-linked glycolipids for recognition by invariant NKT cells

Research paper thumbnail of Gram-positive bacteria: a major microbial ‘turn-on’ for invariant NKT cells

Immunotherapy, 2012

Invariant NKT (iNKT) cells are evolution‐ arily conserved immunoregulatory cells that are charact... more Invariant NKT (iNKT) cells are evolution‐ arily conserved immunoregulatory cells that are characterized by an extremely restricted T‐cell antigen receptor (TCR) repertoire (Va14–Ja18 in mice and Va24–Ja18 in humans) and that can be activated by glyco‐ lipid antigen presented in the context of the nonpolymorphic MHC class I‐like molecule CD1d [1]. It is well known that iNKT cells can participate in antimicrobial immune responses. In some cases, this results from activation of iNKT by inflammatory cyto‐ kines and/or self‐antigen presented by CD1d; in other cases (e.g., infection with Sphingomonas species and Borrelia burgdorferi), this directly results from the pre‐ sentation of microbial glycolipids by CD1d to iNKT [1]. As in general neither of these microbes causes lethal diseases, it is still a matter of debate what exactly is the driv‐ ing evolutionary force behind the strongly c onserved iNKT–CD1d recognition system. In a recent paper in Nature Immunology, Kinjo et al. provide compelling evidence that iNKT cells directly recognize glycolipid antigens from highly pathogenic group B Streptococcus and Streptococcus pneumoniae in a CD1d‐restricted and invariant TCR (iTCR)‐dependent fashion [2]. These data are in accordance with an earlier obser‐ vation that infection with S. pneumoniae resulted in increased bacterial growth and reduced survival in iNKT‐deficient com‐ pared with wild‐type mice [3]. Glycolipids of S. pneumoniae and group B Streptococcus were found to be diacylglycerol based and contained a cis‐vaccenic acid that, in order to be an iNKT agonist, was exclusively required to be in the sn‐2 glycerol position. cis‐vaccenic acid, which is uncommon in mammalian cells and therefore considered a microbial structure, was found to bind in the A’ antigen‐binding pocket of CD1d encircling the A’ pole in a clockwise fashion, allowing the remaining fatty acid to bind in the opposite F’ pocket leaving the a‐ano‐ meric glucose exposed for TCR recogni‐ tion. In this way, the unique hydrophobic lipid chains of the S. pneumoniae antigens contribute to the iTCR epitope (and iNKT activation) by defining the positioning of the exposed sugar. This study highlights not only the role of iNKT cells in the immune response against pathogens that are of worldwide clinical significance, and the stringent require‐ ments for both lipid and sugar structures in allowing interactions between CD1d and iNKT, but also suggests that the iTCR may have been evolutionarily conserved owing to its ability to recognize a set of widely dis‐ tributed glycolipids that are considered an essential part of many microbes, including potentially life‐threatening strains.

Research paper thumbnail of Bispecific antibody platforms for cancer immunotherapy

Critical Reviews in Oncology/Hematology, 2014

Over the past decades advances in bioengineering and expanded insight in tumor immunology have re... more Over the past decades advances in bioengineering and expanded insight in tumor immunology have resulted in the emergence of novel bispecific antibody (bsAb) constructs that are capable of redirecting immune effector cells to the tumor microenvironment. (Pre-) clinical studies of various bsAb constructs have shown impressive results in terms of immune effector cell retargeting, target dependent activation and the induction of anti-tumor responses. This review summarizes recent advances in the field of bsAb-therapy and limitations that were encountered. Furthermore, we will discuss potential future developments that can be expected to take the bsAb approach successfully forward.

Research paper thumbnail of Priming of PRAME- and WT1-specific CD8+T cells in healthy donors but not in AML patients in complete remission

OncoImmunology, 2013

Active immunotherapy may prevent the relapse of acute myeloid leukemia (AML) by inducing leukemia... more Active immunotherapy may prevent the relapse of acute myeloid leukemia (AML) by inducing leukemia-specific t cells. Here, we investigated whether Wilms' tumor 1 (Wt1) and preferentially expressed antigen in melanoma (prAMe)-specific t cells could be induced upon the priming of healthy donor-and AML patient-derived t cells with HLA-A2-matched, peptide-loaded allogeneic dendritic cells. AML-reactive, tetramer (tm)-binding and interferon-producing, cytotoxic t lymphocytes specific for prAMe could readily be isolated from healthy individuals and maintained in culture. In this setting, priming efficacy was significantly higher for prAMe than for Wt1. the priming of t cells from patient-derived material proved to be near-to-impossible: No leukemia-associated antigen (LAA)-specific t cell could be primed in 4 patients that had recently achieved a complete response (Cr), and in only 1 out of 3 patients exhibiting a sustained Cr we did observe Wt1-specific t cells, though with a low frequency. these findings suggest that the functionality and/or repertoire of t cells differ in healthy subjects and AML patients in Cr, and may have repercussions for the implementation of active vaccination approaches against AML.

Research paper thumbnail of Functional characterization of a STAT3-dependent dendritic cell-derived CD14+cell population arising upon IL-10-driven maturation

Research paper thumbnail of Specific tumor targeting and activation of Vγ9Vδ2 T cells by bi-specific nanobodies

Journal for ImmunoTherapy of Cancer, 2014

Research paper thumbnail of The effects of pre-operative administration of CpG 7909 on dendritic and T cell subsets in the sentinel lymph node of stage I/II melanoma patients

Research paper thumbnail of Human dendritic cell line models for DC differentiation and clinical DC vaccination studies

Journal of Leukocyte Biology, 2008

Research paper thumbnail of Prolonged Maturation and Enhanced Transduction of Dendritic Cells Migrated from Human Skin Explants After In Situ Delivery of CD40-Targeted Adenoviral Vectors

The Journal of Immunology, 2002

Therapeutic tumor vaccination with viral vectors or naked DNA, carrying the genetic code for tumo... more Therapeutic tumor vaccination with viral vectors or naked DNA, carrying the genetic code for tumor-associated Ags, critically depends on the in vivo transduction of dendritic cells (DC). Transfection of predominantly nonprofessional APC and only small numbers of DC may hamper proper T cell activation. Aim of this study was, therefore, the targeted, selective, and enhanced in situ transduction of DC. A human skin explant model was used to explore targeted transduction of cutaneous DC after intradermal injection of a bispecific Ab conjugate to link adenoviral (Ad) vectors directly to CD40 on the DC surface. A significantly enhanced transduction efficiency and selectivity, and an increased activation state of migrating DC were thus achieved. Moreover, DC transduced by CD40-targeted Ad maintained their Ag-specific CTL-stimulatory ability for up to 1 wk after the start of migration, in contrast to DC transduced by untargeted Ad, which had lost this capacity by that time. Because DC targeting in vivo might obviate the need for the in vitro culture of autologous DC for adoptive transfer, CD40-targeted Ad vectors constitute a promising new vaccine modality for tumor immunotherapy.