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Article ; Online: Inhibition of SUMOylation enhances DNA hypomethylating drug efficacy to reduce outgrowth of hematopoietic malignancies.

Kroonen, Jessie S / de Graaf, Ilona J / Kumar, Sumit / Remst, Dennis F G / Wouters, Anne K / Heemskerk, Mirjam H M / Vertegaal, Alfred C O

Leukemia

2023 Volume 37, Issue 4, Page(s) 864–876

Abstract: Combination therapies targeting malignancies aim to increase treatment efficacy and reduce toxicity. Hypomethylating drug 5-Aza-2'-deoxycytidine (5-Aza-2') enhances transcription of tumor suppressor genes and induces replication errors via entrapment of ... ...

Abstract	Combination therapies targeting malignancies aim to increase treatment efficacy and reduce toxicity. Hypomethylating drug 5-Aza-2'-deoxycytidine (5-Aza-2') enhances transcription of tumor suppressor genes and induces replication errors via entrapment of DNMT1, yielding DNA-protein crosslinks. Post-translational modification by SUMO plays major roles in the DNA damage response and is required for degradation of entrapped DNMT1. Here, we combine SUMOylation inhibitor TAK981 and DNA-hypomethylating agent 5-Aza-2'-deoxycytidine to improve treatment of MYC driven hematopoietic malignancies, since MYC overexpressing tumors are sensitive to SUMOylation inhibition. We studied the classical MYC driven malignancy Burkitt lymphoma, as well as diffuse large B-cell lymphoma (DLBCL) with and without MYC translocation. SUMO inhibition prolonged the entrapment of DNMT1 to DNA, resulting in DNA damage. An increase in DNA damage was observed in cells co-treated with TAK981 and 5-Aza-2'. Both drugs synergized to reduce cell proliferation in vitro in a B cell lymphoma cell panel, including Burkitt lymphoma and DLBCL. In vivo experiments combining TAK981 (25 mg/kg) and 5-Aza-2' (2.5 mg/kg) showed a significant reduction in outgrowth of Burkitt lymphoma in an orthotopic xenograft model. Our results demonstrate the potential of tailored combination of drugs, based on insight in molecular mechanisms, to improve the efficacy of cancer therapies.
MeSH term(s)	Humans ; Burkitt Lymphoma/drug therapy ; Burkitt Lymphoma/genetics ; Burkitt Lymphoma/metabolism ; Decitabine/pharmacology ; Sumoylation ; Azacitidine/pharmacology ; Azacitidine/therapeutic use ; Hematologic Neoplasms ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Lymphoma, Large B-Cell, Diffuse/genetics ; Lymphoma, Large B-Cell, Diffuse/pathology ; DNA/metabolism ; Cell Line, Tumor
Chemical Substances	Decitabine (776B62CQ27) ; Azacitidine (M801H13NRU) ; DNA (9007-49-2)
Language	English
Publishing date	2023-02-15
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/s41375-023-01838-8
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Zs.A 2295: Show issues

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Article ; Online: Self-sufficient primary natural killer cells engineered to express T cell receptors and interleukin-15 exhibit improved effector function and persistence.

van Hees, Els P / Morton, Laura T / Remst, Dennis F G / Wouters, Anne K / Van den Eynde, Astrid / Falkenburg, J H Frederik / Heemskerk, Mirjam H M

Frontiers in immunology

2024 Volume 15, Page(s) 1368290

Abstract: Background: NK cells can be genetically engineered to express a transgenic T-cell receptor (TCR). This approach offers an alternative strategy to target heterogenous tumors, as NK:TCR cells can eradicate both tumor cells with high expression of HLA ... ...

Abstract	Background: NK cells can be genetically engineered to express a transgenic T-cell receptor (TCR). This approach offers an alternative strategy to target heterogenous tumors, as NK:TCR cells can eradicate both tumor cells with high expression of HLA class I and antigen of interest or HLA class I negative tumors. Expansion and survival of NK cells relies on the presence of IL-15. Therefore, autonomous production of IL-15 by NK:TCR cells might improve functional persistence of NK cells. Here we present an optimized NK:TCR product harnessed with a construct encoding for soluble IL-15 (NK:TCR/IL-15), to support their proliferation, persistence and cytotoxic capabilities. Methods: Expression of tumor-specific TCRs in peripheral blood derived NK-cells was achieved following retroviral transduction. NK:TCR/IL-15 cells were compared with NK:TCR cells for autonomous cytokine production, proliferation and survival. NK:BOB1-TCR/IL-15 cells, expressing a HLA-B07:02-restricted TCR against BOB1, a B-cell lineage specific transcription factor highly expressed in all B-cell malignancies, were compared with control NK:BOB1-TCR and NK:CMV-TCR/IL-15 cells for effector function against TCR antigen positive malignant B-cell lines Results:* Viral incorporation of the interleukin-15 gene into engineered NK:TCR cells was feasible and high expression of the TCR was maintained, resulting in pure NK:TCR/IL-15 cell products generated from peripheral blood of multiple donors. Self-sufficient secretion of IL-15 by NK:TCR cells enables engineered NK cells to proliferate Conclusion: This study showed that NK:TCR/IL-15 cells secrete low levels of IL-15 and can proliferate in an environment lacking cytokines. Repeated
MeSH term(s)	Interleukin-15/genetics ; Interleukin-15/immunology ; Interleukin-15/metabolism ; Humans ; Killer Cells, Natural/immunology ; Killer Cells, Natural/metabolism ; Animals ; Mice ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/immunology ; Cytotoxicity, Immunologic ; Cell Proliferation ; Cell Line, Tumor ; Immunotherapy, Adoptive/methods ; Genetic Engineering
Chemical Substances	Interleukin-15 ; Receptors, Antigen, T-Cell ; IL15 protein, human
Language	English
Publishing date	2024-04-16
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.2024.1368290
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Article: Human iPSC-derived preclinical models to identify toxicity of tumor-specific T cells with clinical potential.

van Amerongen, Rosa A / Morton, Laura T / Chaudhari, Umesh G / Remst, Dennis F G / Hagedoorn, Renate S / van den Berg, Cathelijne W / Freund, Christian / Falkenburg, J H Frederik / Heemskerk, Mirjam H M

Molecular therapy. Methods & clinical development

2023 Volume 28, Page(s) 249–261

Abstract: The balance between safety and efficacy of T cell therapies remains challenging and T cell mediated toxicities have occurred. The stringent selection of tumor-specific targets and careful selection of tumor-specific T cells using T cell toxicity ... ...

Abstract	The balance between safety and efficacy of T cell therapies remains challenging and T cell mediated toxicities have occurred. The stringent selection of tumor-specific targets and careful selection of tumor-specific T cells using T cell toxicity screenings are essential.
Language	English
Publishing date	2023-01-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2872938-9
ISSN	2329-0501 ; 2329-0501
ISSN (online)	2329-0501
ISSN	2329-0501
DOI	10.1016/j.omtm.2023.01.005
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Zs.A 7107: Show issues

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Article ; Online: Combining BCMA-targeting CAR T cells with TCR-engineered T-cell therapy to prevent immune escape of multiple myeloma.

Wachsmann, Tassilo L A / Meeuwsen, Miranda H / Remst, Dennis F G / Buchner, Karen / Wouters, Anne K / Hagedoorn, Renate S / Falkenburg, J H Frederik / Heemskerk, Mirjam H M

Blood advances

2023 Volume 7, Issue 20, Page(s) 6178–6183

MeSH term(s)	Humans ; Multiple Myeloma/therapy ; B-Cell Maturation Antigen ; Receptors, Chimeric Antigen/genetics ; T-Lymphocytes ; Cell- and Tissue-Based Therapy
Chemical Substances	B-Cell Maturation Antigen ; Receptors, Chimeric Antigen
Language	English
Publishing date	2023-08-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2023010410
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Zs.A 7153: Show issues

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Article ; Online: Antibody-mediated delivery of viral epitopes to redirect EBV-specific CD8

van der Wulp, Willemijn / Remst, Dennis F G / Kester, Michel G D / Hagedoorn, Renate S / Parren, Paul W H I / van Kasteren, Sander I / Schuurman, Janine / Hoeben, Rob C / Ressing, Maaike E / Bleijlevens, Boris / Heemskerk, Mirjam H M

Cancer gene therapy

2023 Volume 31, Issue 1, Page(s) 58–68

Abstract: Antibody-mediated delivery of immunogenic epitopes to redirect virus-specific ... ...

Abstract	Antibody-mediated delivery of immunogenic epitopes to redirect virus-specific CD8
MeSH term(s)	Humans ; CD8-Positive T-Lymphocytes ; Epitopes ; Herpesvirus 4, Human/genetics ; Neoplasms/therapy ; Immunoconjugates ; Epitopes, T-Lymphocyte
Chemical Substances	Epitopes ; Immunoconjugates ; Epitopes, T-Lymphocyte
Language	English
Publishing date	2023-11-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1212513-1
ISSN	1476-5500 ; 0929-1903
ISSN (online)	1476-5500
ISSN	0929-1903
DOI	10.1038/s41417-023-00681-4
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Zs.A 4125: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Broadly applicable TCR-based therapy for multiple myeloma targeting the immunoglobulin J chain.

Meeuwsen, Miranda H / Wouters, Anne K / Wachsmann, Tassilo L A / Hagedoorn, Renate S / Kester, Michel G D / Remst, Dennis F G / van der Steen, Dirk M / de Ru, Arnoud H / van Hees, Els P / Kremer, Martijn / Griffioen, Marieke / van Veelen, Peter A / Falkenburg, J H Frederik / Heemskerk, Mirjam H M

Journal of hematology & oncology

2023 Volume 16, Issue 1, Page(s) 16

Abstract: Background: The immunoglobulin J chain (Jchain) is highly expressed in the majority of multiple myeloma (MM), and Jchain-derived peptides presented in HLA molecules may be suitable antigens for T-cell therapy of MM.: Methods: Using immunopeptidomics, ...

Abstract	Background: The immunoglobulin J chain (Jchain) is highly expressed in the majority of multiple myeloma (MM), and Jchain-derived peptides presented in HLA molecules may be suitable antigens for T-cell therapy of MM. Methods: Using immunopeptidomics, we identified Jchain-derived epitopes presented by MM cells, and pHLA tetramer technology was used to isolate Jchain-specific T-cell clones. Results: We identified T cells specific for Jchain peptides presented in HLA-A1, -A24, -A3, and -A11 that recognized and lysed JCHAIN-positive MM cells. TCRs of the most promising T-cell clones were sequenced, cloned into retroviral vectors, and transferred to CD8 T cells. Jchain TCR T cells recognized target cells when JCHAIN and the appropriate HLA restriction alleles were expressed, while JCHAIN or HLA-negative cells, including healthy subsets, were not recognized. Patient-derived JCHAIN-positive MM samples were also lysed by Jchain TCR T cells. In a preclinical in vivo model for established MM, Jchain-A1, -A24, -A3, and -A11 TCR T cells strongly eradicated MM cells, which resulted in 100-fold lower tumor burden in Jchain TCR versus control-treated mice. Conclusions: We identified TCRs targeting Jchain-derived peptides presented in four common HLA alleles. All four TCRs demonstrated potent preclinical anti-myeloma activity, encouraging further preclinical testing and ultimately clinical development.
MeSH term(s)	Animals ; Mice ; Immunoglobulin J-Chains ; Multiple Myeloma/therapy ; Receptors, Antigen, T-Cell/genetics ; Alleles ; CD8-Positive T-Lymphocytes
Chemical Substances	Immunoglobulin J-Chains ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-02-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2429631-4
ISSN	1756-8722 ; 1756-8722
ISSN (online)	1756-8722
ISSN	1756-8722
DOI	10.1186/s13045-023-01408-6
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Article: Erratum: A library of cancer testis specific T cell receptors for T cell receptor gene therapy.

de Rooij, Marije A J / Remst, Dennis F G / van der Steen, Dirk M / Wouters, Anne K / Hagedoorn, Renate S / Kester, Michel G D / Meeuwsen, Miranda H / Wachsmann, Tassilo L A / de Ru, Arnoud H / van Veelen, Peter A / Verdegaal, Els M E / Falkenburg, J H Frederik / Heemskerk, Mirjam H M

Molecular therapy oncolytics

2023 Volume 31, Page(s) 100738

Abstract: This corrects the article DOI: 10.1016/j.omto.2022.11.007.]. ...

Abstract	[This corrects the article DOI: 10.1016/j.omto.2022.11.007.].
Language	English
Publishing date	2023-10-23
Publishing country	United States
Document type	Published Erratum
ISSN	2372-7705
ISSN	2372-7705
DOI	10.1016/j.omto.2023.100738
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Article ; Online: Comparing CAR and TCR engineered T cell performance as a function of tumor cell exposure.

Wachsmann, Tassilo L A / Wouters, Anne K / Remst, Dennis F G / Hagedoorn, Renate S / Meeuwsen, Miranda H / van Diest, Eline / Leusen, Jeanette / Kuball, Jürgen / Falkenburg, J H Frederik / Heemskerk, Mirjam H M

Oncoimmunology

2022 Volume 11, Issue 1, Page(s) 2033528

Abstract: Chimeric antigen receptor (CAR) T cell therapies have resulted in profound clinical responses in the treatment of CD19-positive hematological malignancies, but a significant proportion of patients do not respond or relapse eventually. As an alternative ... ...

Abstract	Chimeric antigen receptor (CAR) T cell therapies have resulted in profound clinical responses in the treatment of CD19-positive hematological malignancies, but a significant proportion of patients do not respond or relapse eventually. As an alternative to CAR T cells, T cells can be engineered to express a tumor-targeting T cell receptor (TCR). Due to HLA restriction of TCRs, CARs have emerged as a preferred treatment moiety when targeting surface antigens, despite the fact that functional differences between engineered TCR (eTCR) T and CAR T cells remain ill-defined. Here, we compared the activity of CAR T cells versus engineered TCR T cells in targeting the B cell malignancy-associated antigen CD20 as a function of antigen exposure. We found CAR T cells to be more potent effector cells, producing higher levels of cytokines and killing more efficiently than eTCR T cells in a short time frame. However, we revealed that the increase of antigen exposure significantly impaired CAR T cell expansion, a phenotype defined by high expression of coinhibitory molecules and effector differentiation. In contrast, eTCR T cells expanded better than CAR T cells under high antigenic pressure, with lower expression of coinhibitory molecules and maintenance of an early differentiation phenotype, and comparable clearance of tumor cells.
MeSH term(s)	Antigens, CD20/metabolism ; Humans ; Immunotherapy, Adoptive/methods ; Neoplasm Recurrence, Local ; Receptors, Antigen, T-Cell/genetics ; T-Lymphocytes
Chemical Substances	Antigens, CD20 ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2022-02-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2645309-5
ISSN	2162-402X ; 2162-4011
ISSN (online)	2162-402X
ISSN	2162-4011
DOI	10.1080/2162402X.2022.2033528
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Article ; Online: T cell receptor engineering of primary NK cells to therapeutically target tumors and tumor immune evasion.

Morton, Laura T / Wachsmann, Tassilo L A / Meeuwsen, Miranda H / Wouters, Anne K / Remst, Dennis F G / van Loenen, Marleen M / Falkenburg, J H Frederik / Heemskerk, Mirjam H M

Journal for immunotherapy of cancer

2022 Volume 10, Issue 3

Abstract: Background: T cell receptor (TCR)-engineered cells can be powerful tools in the treatment of malignancies. However, tumor resistance by Human Leukocyte antigen (HLA) class I downregulation can negatively impact the success of any TCR-mediated cell ... ...

Abstract	Background: T cell receptor (TCR)-engineered cells can be powerful tools in the treatment of malignancies. However, tumor resistance by Human Leukocyte antigen (HLA) class I downregulation can negatively impact the success of any TCR-mediated cell therapy. Allogeneic natural killer (NK) cells have demonstrated efficacy and safety against malignancies without inducing graft-versus-host-disease, highlighting the feasibility for an 'off the shelf' cellular therapeutic. Furthermore, primary NK cells can target tumors using a broad array of intrinsic activation mechanisms. In this study, we combined the antitumor effector functions of NK cells with TCR engineering (NK-TCR), creating a novel therapeutic strategy to avoid TCR-associated immune resistance. Methods: BOB1, is a transcription factor highly expressed in all healthy and malignant B cell lineages, including multiple myeloma (MM). Expression of an HLA-B07:02 restricted BOB1-specifc TCR in peripheral blood-derived NK cells was achieved following a two-step retroviral transduction protocol. NK-TCR was then compared with TCR-negative NK cells and CD8-T cells expressing the same TCR for effector function against HLA-B07:02+ B-cell derived lymphoblastoid cell lines (B-LCL), B-cell acute lymphoblastic leukemia and MM cell lines in vitro and in vivo. Results: Firstly, TCR could be reproducibly expressed in NK cells isolated from the peripheral blood of multiple healthy donors generating pure NK-TCR cell products. Secondly, NK-TCR demonstrated antigen-specific effector functions against malignancies which were previously resistant to NK-mediated lysis and enhanced NK efficacy in vivo using a preclinical xenograft model of MM. Moreover, antigen-specific cytotoxicity and cytokine production of NK-TCR was comparable to CD8 T cells expressing the same TCR. Finally, in a model of HLA-class I loss, tumor cells with B2M KO were lysed by NK-TCR in an NK-mediated manner but were resistant to T-cell based killing. Conclusion: NK-TCR cell therapy enhances NK cell efficacy against tumors through additional TCR-mediated lysis. Furthermore, the dual efficacy of NK-TCR permits the specific targeting of tumors and the associated TCR-associated immune resistance, making NK-TCR a unique cellular therapeutic.
MeSH term(s)	Histocompatibility Antigens Class I ; Humans ; Killer Cells, Natural ; Multiple Myeloma ; Receptors, Antigen, T-Cell/genetics ; Tumor Escape
Chemical Substances	Histocompatibility Antigens Class I ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2022-03-14
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-2021-003715
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Article ; Online: PRAME and CTCFL-reactive TCRs for the treatment of ovarian cancer.

van Amerongen, Rosa A / Tuit, Sander / Wouters, Anne K / van de Meent, Marian / Siekman, Sterre L / Meeuwsen, Miranda H / Wachsmann, Tassilo L A / Remst, Dennis F G / Hagedoorn, Renate S / van der Steen, Dirk M / de Ru, Arnoud H / Verdegaal, Els M E / van Veelen, Peter A / Falkenburg, J H Frederik / Heemskerk, Mirjam H M

Frontiers in immunology

2023 Volume 14, Page(s) 1121973

Abstract: Recurrent disease emerges in the majority of patients with ovarian cancer (OVCA). Adoptive T-cell therapies with T-cell receptors (TCRs) targeting tumor-associated antigens (TAAs) are considered promising solutions for less-immunogenic 'cold' ovarian ... ...

Abstract	Recurrent disease emerges in the majority of patients with ovarian cancer (OVCA). Adoptive T-cell therapies with T-cell receptors (TCRs) targeting tumor-associated antigens (TAAs) are considered promising solutions for less-immunogenic 'cold' ovarian tumors. In order to treat a broader patient population, more TCRs targeting peptides derived from different TAAs binding in various HLA class I molecules are essential. By performing a differential gene expression analysis using mRNA-seq datasets, PRAME, CTCFL and CLDN6 were selected as strictly tumor-specific TAAs, with high expression in ovarian cancer and at least 20-fold lower expression in all healthy tissues of risk. In primary OVCA patient samples and cell lines we confirmed expression and identified naturally expressed TAA-derived peptides in the HLA class I ligandome. Subsequently, high-avidity T-cell clones recognizing these peptides were isolated from the allo-HLA T-cell repertoire of healthy individuals. Three PRAME TCRs and one CTCFL TCR of the most promising T-cell clones were sequenced, and transferred to CD8+ T cells. The PRAME TCR-T cells demonstrated potent and specific antitumor reactivity
MeSH term(s)	Humans ; Female ; Receptors, Antigen, T-Cell ; Antigens, Neoplasm ; CD8-Positive T-Lymphocytes ; Ovarian Neoplasms/therapy ; Ovarian Neoplasms/metabolism ; Peptides/metabolism ; DNA-Binding Proteins/metabolism
Chemical Substances	Receptors, Antigen, T-Cell ; Antigens, Neoplasm ; Peptides ; CTCFL protein, human ; DNA-Binding Proteins ; PRAME protein, human
Language	English
Publishing date	2023-03-21
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.2023.1121973
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