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Article ; Online: Immunotherapy Goes Local: The Central Role of Lymph Nodes in Driving Tumor Infiltration and Efficacy.

van Pul, Kim M / Fransen, Marieke F / van de Ven, Rieneke / de Gruijl, Tanja D

2021 Volume 12, Page(s) 643291

Abstract: Immune checkpoint blockade (ICB) has changed the therapeutic landscape of oncology but its impact is limited by primary or secondary resistance. ICB resistance has been related to a lack of T cells infiltrating into the tumor. Strategies to overcome this ...

Abstract	Immune checkpoint blockade (ICB) has changed the therapeutic landscape of oncology but its impact is limited by primary or secondary resistance. ICB resistance has been related to a lack of T cells infiltrating into the tumor. Strategies to overcome this hurdle have so far focused on the tumor microenvironment, but have mostly overlooked the role of tumor-draining lymph nodes (TDLN). Whereas for CTLA-4 blockade TDLN have long since been implicated due to its perceived mechanism-of-action involving T cell priming, only recently has evidence been emerging showing TDLN to be vital for the efficacy of PD-1 blockade as well. TDLN are targeted by developing tumors to create an immune suppressed pre-metastatic niche which can lead to priming of dysfunctional antitumor T cells. In this review, we will discuss the evidence that therapeutic targeting of TDLN may ensure sufficient antitumor T cell activation and subsequent tumor infiltration to facilitate effective ICB. Indeed, waves of tumor-specific, proliferating stem cell-like, or progenitor exhausted T cells, either newly primed or reinvigorated in TDLN, are vital for PD-1 blockade efficacy. Both tumor-derived migratory dendritic cell (DC) subsets and DC subsets residing in TDLN, and an interplay between them, have been implicated in the induction of these T cells, their imprinting for homing and subsequent tumor control. We propose that therapeutic approaches, involving local delivery of immune modulatory agents for optimal access to TDLN, aimed at overcoming hampered DC activation, will enable ICB by promoting T cell recruitment to the tumor, both in early and in advanced stages of cancer.
MeSH term(s)	Humans ; Immunity, Cellular ; Immunotherapy ; Lymph Nodes/immunology ; Lymph Nodes/pathology ; Lymphatic Metastasis ; Lymphocytes, Tumor-Infiltrating/immunology ; Lymphocytes, Tumor-Infiltrating/pathology ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/therapy ; T-Lymphocytes/immunology ; T-Lymphocytes/pathology
Language	English
Publishing date	2021-03-01
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.643291
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Article: Palmitoylated antigens for the induction of anti-tumor CD8

Stolk, Dorian A / Horrevorts, Sophie K / Schetters, Sjoerd T T / Kruijssen, Laura J W / Duinkerken, Sanne / Keuning, Eelco / Ambrosini, Martino / Kalay, Hakan / van de Ven, Rieneke / Garcia-Vallejo, Juan J / de Gruijl, Tanja D / van Vliet, Sandra J / van Kooyk, Yvette

Molecular therapy oncolytics

2021 Volume 21, Page(s) 315–328

Abstract: Induction of tumor-specific cytotoxic ... ...

Abstract	Induction of tumor-specific cytotoxic CD8
Language	English
Publishing date	2021-04-29
Publishing country	United States
Document type	Journal Article
ISSN	2372-7705
ISSN	2372-7705
DOI	10.1016/j.omto.2021.04.009
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Article ; Online: Tumor-educated T

Kos, Kevin / Aslam, Muhammad A / van de Ven, Rieneke / Wellenstein, Max D / Pieters, Wietske / van Weverwijk, Antoinette / Duits, Danique E M / van Pul, Kim / Hau, Cheei-Sing / Vrijland, Kim / Kaldenbach, Daphne / Raeven, Elisabeth A M / Quezada, Sergio A / Beyaert, Rudi / Jacobs, Heinz / de Gruijl, Tanja D / de Visser, Karin E

Cell reports

2022 Volume 38, Issue 9, Page(s) 110447

Abstract: Breast cancer is accompanied by systemic immunosuppression, which facilitates metastasis formation, but how this shapes organotropism of metastasis is poorly understood. Here, we investigate the impact of mammary tumorigenesis on regulatory T cells ( ... ...

Abstract	Breast cancer is accompanied by systemic immunosuppression, which facilitates metastasis formation, but how this shapes organotropism of metastasis is poorly understood. Here, we investigate the impact of mammary tumorigenesis on regulatory T cells (T
MeSH term(s)	Animals ; Breast Neoplasms/pathology ; Carcinogenesis/pathology ; Female ; Humans ; Killer Cells, Natural/pathology ; Lymph Nodes ; Lymphatic Metastasis/pathology ; Mice
Language	English
Publishing date	2022-02-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2022.110447
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Article ; Online: Oncolytic Adenovirus ORCA-010 Activates Proinflammatory Myeloid Cells and Facilitates T Cell Recruitment and Activation by PD-1 Blockade in Melanoma.

Milenova, Ioanna / Lopez Gonzalez, Marta / Quixabeira, Dafne C A / Santos, Joao Manuel / Cervera-Carrascon, Victor / Dong, Wenliang / Hemminki, Akseli / van Beusechem, Victor W / van de Ven, Rieneke / de Gruijl, Tanja D

Human gene therapy

2021 Volume 32, Issue 3-4, Page(s) 178–191

Abstract: Immune checkpoint inhibitors have advanced the treatment of melanoma. Nevertheless, a majority of patients are resistant, or develop resistance, to immune checkpoint blockade, which may be related to prevailing immune suppression by myeloid regulatory ... ...

Abstract	Immune checkpoint inhibitors have advanced the treatment of melanoma. Nevertheless, a majority of patients are resistant, or develop resistance, to immune checkpoint blockade, which may be related to prevailing immune suppression by myeloid regulatory cells in the tumor microenvironment (TME). ORCA-010 is a novel oncolytic adenovirus that selectively replicates in, and lyses, cancer cells. We previously showed that ORCA-010 can activate melanoma-exposed conventional dendritic cells (cDCs). To study the effect of ORCA-010 on melanoma-conditioned macrophage development, we used an
MeSH term(s)	Adenoviridae/genetics ; Animals ; CD8-Positive T-Lymphocytes ; Cell Line, Tumor ; Humans ; Macrophages ; Melanoma, Experimental/therapy ; Mice ; Programmed Cell Death 1 Receptor ; Tumor Microenvironment
Chemical Substances	Programmed Cell Death 1 Receptor
Language	English
Publishing date	2021-01-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1028152-6
ISSN	1557-7422 ; 1043-0342
ISSN (online)	1557-7422
ISSN	1043-0342
DOI	10.1089/hum.2020.277
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Article ; Online: A Bispecific γδ T-cell Engager Targeting EGFR Activates a Potent Vγ9Vδ2 T cell-Mediated Immune Response against EGFR-Expressing Tumors.

King, Lisa A / Toffoli, Elisa C / Veth, Myrthe / Iglesias-Guimarais, Victoria / Slot, Manon C / Amsen, Derk / van de Ven, Rieneke / Derks, Sarah / Fransen, Marieke F / Tuynman, Jurriaan B / Riedl, Thilo / Roovers, Rob C / Adang, Anton E P / Ruben, Jurjen M / Parren, Paul W H I / de Gruijl, Tanja D / van der Vliet, Hans J

Cancer immunology research

2023 Volume 11, Issue 9, Page(s) 1237–1252

Abstract: Vγ9Vδ2 T cells are effector cells with proven antitumor efficacy against a broad range of cancers. This study aimed to assess the antitumor activity and safety of a bispecific antibody directing Vγ9Vδ2 T cells to EGFR-expressing tumors. An EGFR-Vδ2 ... ...

Abstract	Vγ9Vδ2 T cells are effector cells with proven antitumor efficacy against a broad range of cancers. This study aimed to assess the antitumor activity and safety of a bispecific antibody directing Vγ9Vδ2 T cells to EGFR-expressing tumors. An EGFR-Vδ2 bispecific T-cell engager (bsTCE) was generated, and its capacity to activate Vγ9Vδ2 T cells and trigger antitumor activity was tested in multiple in vitro, in vivo, and ex vivo models. Studies to explore safety were conducted using cross-reactive surrogate engagers in nonhuman primates (NHP). We found that Vγ9Vδ2 T cells from peripheral blood and tumor specimens of patients with EGFR+ cancers had a distinct immune checkpoint expression profile characterized by low levels of PD-1, LAG-3, and TIM-3. Vγ9Vδ2 T cells could be activated by EGFR-Vδ2 bsTCEs to mediate lysis of various EGFR+ patient-derived tumor samples, and substantial tumor growth inhibition and improved survival were observed in in vivo xenograft mouse models using peripheral blood mononuclear cells (PBMC) as effector cells. EGFR-Vδ2 bsTCEs exerted preferential activity toward EGFR+ tumor cells and induced downstream activation of CD4+ and CD8+ T cells and natural killer (NK) cells without concomitant activation of suppressive regulatory T cells observed with EGFR-CD3 bsTCEs. Administration of fully cross-reactive and half-life extended surrogate engagers to NHPs did not trigger signals in the safety parameters that were assessed. Considering the effector and immune-activating properties of Vγ9Vδ2 T cells, the preclinical efficacy data and acceptable safety profile reported here provide a solid basis for testing EGFR-Vδ2 bsTCEs in patients with EGFR+ malignancies.
MeSH term(s)	Humans ; Mice ; Animals ; Leukocytes, Mononuclear ; Receptors, Antigen, T-Cell, gamma-delta ; Neoplasms/drug therapy ; Antibodies, Bispecific/pharmacology ; Antibodies, Bispecific/therapeutic use ; Immunity ; ErbB Receptors ; Lymphocyte Activation
Chemical Substances	Receptors, Antigen, T-Cell, gamma-delta ; Antibodies, Bispecific ; ErbB Receptors (EC 2.7.10.1) ; EGFR protein, human (EC 2.7.10.1)
Language	English
Publishing date	2023-06-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-23-0189
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Article ; Online: Comparative phenotypic and functional analysis of migratory dendritic cell subsets from human oral mucosa and skin.

Kosten, Ilona Jennifer / van de Ven, Rieneke / Thon, Maria / Gibbs, Susan / de Gruijl, Tanja D

PloS one

2017 Volume 12, Issue 7, Page(s) e0180333

Abstract: Antigen exposure to oral mucosa is generally thought to lead to immune tolerance induction. However, very little is known about the subset composition and function of dendritic cells (DC) migrating from human oral mucosa. Here we show that migratory DC ... ...

Abstract	Antigen exposure to oral mucosa is generally thought to lead to immune tolerance induction. However, very little is known about the subset composition and function of dendritic cells (DC) migrating from human oral mucosa. Here we show that migratory DC from healthy human gingival explants consist of the same phenotypic subsets in the same frequency distribution as DC migrating from human skin. The gingival CD1a+ Langerhans cell and interstitial DC subsets lacked CXCR4 expression in contrast to their cutaneous counterparts, pointing to different migration mechanisms, consistent with previous observations in constructed skin and gingival equivalents. Remarkably, without any exogenous conditioning, gingival explants released higher levels of inflammatory cytokines than human skin explants, resulting in higher DC migration rates and a superior ability of migrated DC to prime allogeneic T cells and to induce type-1 effector T cell differentiation. From these observations we conclude that rather than an intrinsic ability to induce T cell tolerance, DC migrating from oral mucosa may have a propensity to induce effector T cell immunity and maintain a high state of alert against possible pathogenic intruders in the steady state. These findings may have implications for oral immunization strategies.
MeSH term(s)	Antigens, CD1/metabolism ; Cell Differentiation ; Cell Movement ; Cytokines/metabolism ; Dendritic Cells/cytology ; Dendritic Cells/immunology ; Humans ; Langerhans Cells/cytology ; Langerhans Cells/immunology ; Mouth Mucosa/cytology ; Mouth Mucosa/metabolism ; Phenotype ; Receptors, CXCR4/metabolism ; Skin/cytology ; Skin/metabolism ; T-Lymphocytes/immunology
Chemical Substances	Antigens, CD1 ; CD1a antigen ; CXCR4 protein, human ; Cytokines ; Receptors, CXCR4
Language	English
Publishing date	2017
Publishing country	United States
Document type	Comparative Study ; Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0180333
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Article ; Online: Breast cancer-induced immune suppression in the sentinel lymph node is effectively countered by CpG-B in conjunction with inhibition of the JAK2/STAT3 pathway.

van Pul, Kim M / Vuylsteke, Ronald J C L M / de Beijer, Monique T A / van de Ven, Rieneke / van den Tol, M Petrousjka / Stockmann, Hein B A C / de Gruijl, Tanja D

Journal for immunotherapy of cancer

2020 Volume 8, Issue 2

Abstract: Background: We previously showed selectively hampered activation of lymph node-resident (LNR) dendritic cell (DC) subsets in the breast cancer (BrC) sentinel lymph node (SLN) to precede a state of profound T cell anergy. Reactivating these DC subsets by ...

Abstract	Background: We previously showed selectively hampered activation of lymph node-resident (LNR) dendritic cell (DC) subsets in the breast cancer (BrC) sentinel lymph node (SLN) to precede a state of profound T cell anergy. Reactivating these DC subsets by intratumoral delivery of the Toll-like receptor-9 (TLR9) agonist CpG-B could potentially offer a promising immune therapeutic strategy to combat this immune suppression and prevent disease spread. Unfortunately, CpG-B can limit its own immune stimulatory activity through direct TLR9-mediated activation of signal transducer and activator of transcription 3 (STAT3), pinpointed as a key regulator of immune suppression in the tumor microenvironment. Here, we have investigated whether in vitro exposure to CpG-B, with or without simultaneous inhibition of STAT3 signaling, could overcome immune suppression in BrC SLN. Methods: Immune modulatory effects of CpG-B (CPG7909) with or without the JAK2/STAT3 inhibitor (STAT3i) AG490 were assessed in ex vivo cultured BrC SLN-derived single-cell suspensions (N=29). Multiparameter flow cytometric analyses were conducted for DC and T cell subset characterization and assessment of (intracellular) cytokine profiles. T cell reactivity against the BrC-associated antigen Mammaglobin-A was determined by means of interferon-γ ELISPOT assay. Results: Although CpG-B alone induced activation of all DC subsets, combined inhibition of the JAK2/STAT3 pathway resulted in superior DC maturation (ie, increased CD83 expression), with most profound activation and maturation of LNR DC subsets. Furthermore, combined CpG-B and JAK2/STAT3 inhibition promoted Th1 skewing by counterbalancing the CpG-induced Th2/regulatory T cell response and significantly enhanced Mammaglobin-A specific T cell reactivity. Conclusion: Ex vivo immune modulation of the SLN by CpG-B and simultaneous JAK2/STAT3 inhibition can effectively overcome BrC-induced immune suppression by preferential activation of LNR DC, ultimately restoring type 1-mediated antitumor immunity, thereby securing a BrC-specific T cell response. These findings provide a clear rationale for clinical exploration of SLN-immune potentiation through local CpG/STAT3i administration in patients with BrC.
MeSH term(s)	Breast Neoplasms/immunology ; Breast Neoplasms/pathology ; Dendritic Cells/immunology ; Female ; Humans ; Immunomodulation/immunology ; STAT3 Transcription Factor/metabolism ; Sentinel Lymph Node/immunology ; Tumor Microenvironment
Chemical Substances	STAT3 Transcription Factor ; STAT3 protein, human
Language	English
Publishing date	2020-09-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2020-000761
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Article ; Online: A Bispecific Antibody Antagonizes Prosurvival CD40 Signaling and Promotes Vγ9Vδ2 T cell-Mediated Antitumor Responses in Human B-cell Malignancies.

de Weerdt, Iris / Lameris, Roeland / Scheffer, George L / Vree, Jana / de Boer, Renate / Stam, Anita G / van de Ven, Rieneke / Levin, Mark-David / Pals, Steven T / Roovers, Rob C / Parren, Paul W H I / de Gruijl, Tanja D / Kater, Arnon P / van der Vliet, Hans J

Cancer immunology research

2020 Volume 9, Issue 1, Page(s) 50–61

Abstract: Novel T cell-based therapies for the treatment of B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), are thought to have strong potential. Progress, however, has been hampered by low efficacy and high toxicity. ... ...

Abstract	Novel T cell-based therapies for the treatment of B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), are thought to have strong potential. Progress, however, has been hampered by low efficacy and high toxicity. Tumor targeting by Vγ9Vδ2 T cells, a conserved T-cell subset with potent intrinsic antitumor properties, mediated by a bispecific antibody represents a novel approach promising high efficacy with limited toxicity. Here, we describe the generation of a bispecific Vγ9Vδ2 T-cell engager directed against CD40, which, due to its overexpression and biological footprint in malignant B cells, represents an attractive target. The CD40-targeting moiety of the bispecific antibody was selected because it can prevent CD40L-induced prosurvival signaling and reduce CD40-mediated resistance of CLL cells to venetoclax. Selective activation of Vγ9Vδ2 T cells in the presence of CD40
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Animals ; Antibodies, Bispecific/immunology ; Antibodies, Bispecific/pharmacology ; CD40 Antigens/immunology ; Cell Line, Tumor ; Female ; HEK293 Cells ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/immunology ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; Lymphocyte Activation/drug effects ; Male ; Mice ; Mice, Inbred NOD ; Middle Aged ; Signal Transduction/drug effects ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
Chemical Substances	Antibodies, Bispecific ; CD40 Antigens
Language	English
Publishing date	2020-11-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-20-0138
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Article ; Online: Lipo-Based Vaccines as an Approach to Target Dendritic Cells for Induction of T- and iNKT Cell Responses.

Stolk, Dorian A / de Haas, Aram / Vree, Jana / Duinkerken, Sanne / Lübbers, Joyce / van de Ven, Rieneke / Ambrosini, Martino / Kalay, Hakan / Bruijns, Sven / van der Vliet, Hans J / de Gruijl, Tanja D / van Kooyk, Yvette

Frontiers in immunology

2020 Volume 11, Page(s) 990

Abstract: In this study we developed a liposome-based vaccine containing palmitoylated synthetic long peptides (SLP) and alpha galactosylceramide (αGC) to specifically target dendritic cells (DC) for activation of both innate (invariant natural killer T-cells [ ... ...

Abstract	In this study we developed a liposome-based vaccine containing palmitoylated synthetic long peptides (SLP) and alpha galactosylceramide (αGC) to specifically target dendritic cells (DC) for activation of both innate (invariant natural killer T-cells [iNKT]) and adaptive (CD8
MeSH term(s)	Adaptive Immunity/drug effects ; CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Cancer Vaccines/immunology ; Cancer Vaccines/pharmacology ; Cells, Cultured ; Dendritic Cells/drug effects ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Galactosylceramides/immunology ; Galactosylceramides/pharmacology ; Humans ; Immunity, Innate/drug effects ; Lewis Blood Group Antigens/immunology ; Lewis Blood Group Antigens/pharmacology ; Liposomes ; Lymphocyte Activation/drug effects ; Melanoma/drug therapy ; Melanoma/immunology ; Melanoma/metabolism ; Natural Killer T-Cells/drug effects ; Natural Killer T-Cells/immunology ; Natural Killer T-Cells/metabolism ; Peptides/immunology ; Peptides/pharmacology ; Skin/drug effects ; Skin/immunology ; Skin/metabolism ; Skin Neoplasms/drug therapy ; Skin Neoplasms/immunology ; Skin Neoplasms/metabolism ; Tissue Culture Techniques
Chemical Substances	Cancer Vaccines ; Galactosylceramides ; Lewis Blood Group Antigens ; Lewis Y antigen ; Liposomes ; Peptides ; alpha-galactosylceramide
Language	English
Publishing date	2020-05-27
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.00990
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Article ; Online: Chapter six--Adenovirus-based immunotherapy of cancer: promises to keep.

de Gruijl, Tanja D / van de Ven, Rieneke

Advances in cancer research

2012 Volume 115, Page(s) 147–220

Abstract: Progress in vector design and an increased knowledge of mechanisms underlying tumor-induced immune suppression have led to a new and promising generation of Adenovirus (Ad)-based immunotherapies, which are discussed in this review. As vaccine vehicles Ad ...

Abstract	Progress in vector design and an increased knowledge of mechanisms underlying tumor-induced immune suppression have led to a new and promising generation of Adenovirus (Ad)-based immunotherapies, which are discussed in this review. As vaccine vehicles Ad vectors (AdVs) have been clinically evaluated and proven safe, but a major limitation of the commonly used Ad5 serotype is neutralization by preexistent or rapidly induced immune responses. Genetic modifications in the Ad capsid can reduce intrinsic immunogenicity and facilitate escape from antibody-mediated neutralization. Further modification of the Ad hexon and fiber allows for liver and scavenger detargeting and selective targeting of, for example, dendritic cells. These next-generation Ad vaccines with enhanced efficacy are now becoming available for testing as tumor vaccines. In addition, AdVs encoding immune-modulating products may be used to convert the tumor microenvironment from immune-suppressive and proinvasive to proinflammatory, thus facilitating cell-mediated effector functions that can keep tumor growth and invasion in check. Oncolytic AdVs, that selectively replicate in tumor cells and induce an immunogenic form of cell death, can also be armed with immune-activating transgenes to amplify primed antitumor immune responses. These novel immunotherapy strategies, employing highly efficacious AdVs in optimized configurations, show great promise and warrant clinical exploration.
MeSH term(s)	Adenoviridae/genetics ; Animals ; Cancer Vaccines/genetics ; Capsid Proteins/chemistry ; Clinical Trials as Topic ; Dendritic Cells/cytology ; Genetic Engineering ; Genetic Therapy/methods ; Genetic Vectors ; Humans ; Immunotherapy/methods ; Mice ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/therapy ; Neutralization Tests
Chemical Substances	Cancer Vaccines ; Capsid Proteins
Language	English
Publishing date	2012
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	127-2
ISSN	2162-5557 ; 0065-230X
ISSN (online)	2162-5557
ISSN	0065-230X
DOI	10.1016/B978-0-12-398342-8.00006-9
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