10 results on '"Meeuwsen MH"'
Search Results
2. Erratum: A library of cancer testis specific T cell receptors for T cell receptor gene therapy.
- Author
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de Rooij MAJ, Remst DFG, van der Steen DM, Wouters AK, Hagedoorn RS, Kester MGD, Meeuwsen MH, Wachsmann TLA, de Ru AH, van Veelen PA, Verdegaal EME, Falkenburg JHF, and Heemskerk MHM
- Abstract
[This corrects the article DOI: 10.1016/j.omto.2022.11.007.]., (© 2023 The Author(s).)
- Published
- 2023
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3. PRAME and CTCFL-reactive TCRs for the treatment of ovarian cancer.
- Author
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van Amerongen RA, Tuit S, Wouters AK, van de Meent M, Siekman SL, Meeuwsen MH, Wachsmann TLA, Remst DFG, Hagedoorn RS, van der Steen DM, de Ru AH, Verdegaal EME, van Veelen PA, Falkenburg JHF, and Heemskerk MHM
- Subjects
- Humans, Female, Antigens, Neoplasm, CD8-Positive T-Lymphocytes, Peptides metabolism, DNA-Binding Proteins metabolism, Receptors, Antigen, T-Cell, Ovarian Neoplasms therapy, Ovarian Neoplasms metabolism
- 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 in vitro and in vivo . The CTCFL TCR-T cells efficiently recognized primary patient-derived OVCA cells, and OVCA cell lines treated with demethylating agent 5-aza-2'-deoxycytidine (DAC). The identified PRAME and CTCFL TCRs are promising candidates for the treatment of patients with ovarian cancer, and are an essential addition to the currently used HLA-A*02:01 restricted PRAME TCRs. Our selection of differentially expressed genes, naturally expressed TAA peptides and potent TCRs can improve and broaden the use of T-cell therapies for patients with ovarian cancer or other PRAME or CTCFL expressing cancers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 van Amerongen, Tuit, Wouters, van de Meent, Siekman, Meeuwsen, Wachsmann, Remst, Hagedoorn, van der Steen, de Ru, Verdegaal, van Veelen, Falkenburg and Heemskerk.)
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- 2023
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4. Broadly applicable TCR-based therapy for multiple myeloma targeting the immunoglobulin J chain.
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Meeuwsen MH, Wouters AK, Wachsmann TLA, Hagedoorn RS, Kester MGD, Remst DFG, van der Steen DM, de Ru AH, van Hees EP, Kremer M, Griffioen M, van Veelen PA, Falkenburg JHF, and Heemskerk MHM
- Subjects
- Animals, Mice, Receptors, Antigen, T-Cell genetics, Alleles, CD8-Positive T-Lymphocytes, Immunoglobulin J-Chains, Multiple Myeloma therapy
- 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., (© 2023. The Author(s).)
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- 2023
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5. A library of cancer testis specific T cell receptors for T cell receptor gene therapy.
- Author
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de Rooij MAJ, Remst DFG, van der Steen DM, Wouters AK, Hagedoorn RS, Kester MGD, Meeuwsen MH, Wachsmann TLA, de Ru AH, van Veelen PA, Verdegaal EME, Falkenburg JHF, and Heemskerk MHM
- Abstract
To increase the number of cancer patients that can be treated with T cell receptor (TCR) gene therapy, we aimed to identify a set of high-affinity cancer-specific TCRs targeting different melanoma-associated antigens (MAGEs). In this study, peptides derived from MAGE genes with tumor-specific expression pattern were identified by human leukocyte antigen (HLA) peptidomics. Next, peptide-HLA tetramers were generated, and used to sort MAGE-specific CD8
+ T cell clones from the allogeneic (allo) HLA repertoire of healthy donors. To evaluate the clinical potential, most potent TCRs were sequenced, transferred into peripheral blood-derived CD8+ T cells, and tested for antitumor efficacy. In total we identified, seven MAGE-specific TCRs that effectively target MAGE-A1, MAGE-A3, MAGE-A6, and MAGE-A9 in the context of HLA-A∗01:01, -A∗02:01, -A∗03:01, -B∗07:02, -B∗35:01, or -C∗07:02. TCR gene transfer into CD8⁺ T cells resulted in efficient reactivity against a variety of different tumor types, while no cross-reactivity was detected. In addition, major in vivo antitumor effects of MAGE-A1 specific TCR engineered CD8⁺ T cells were observed in the orthotopic xenograft model for established multiple myeloma. The identification of seven MAGE-specific TCRs expands the pool of cancer patients eligible for TCR gene therapy and increases possibilities for personalized TCR gene therapy., Competing Interests: The authors report no competing interests., (© 2022 The Author(s).)- Published
- 2022
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6. Enhanced antigen cross-presentation in human colorectal cancer-associated fibroblasts through upregulation of the lysosomal protease cathepsin S.
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Harryvan TJ, Visser M, de Bruin L, Plug L, Griffioen L, Mulder A, van Veelen PA, van der Heden van Noort GJ, Jongsma ML, Meeuwsen MH, Wiertz EJ, Santegoets SJ, Hardwick JC, Van Hall T, Neefjes J, Van der Burg SH, Hawinkels LJ, and Verdegaal EM
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- Animals, Cathepsins, Cross-Priming, Humans, Lysosomes metabolism, Mice, Peptide Hydrolases genetics, Peptide Hydrolases metabolism, Up-Regulation, Cancer-Associated Fibroblasts metabolism, Colorectal Neoplasms genetics
- Abstract
Background: Cross-presentation of exogenous antigens in HLA-class I molecules by professional antigen presenting cells (APCs) is crucial for CD8+ T cell function. Recent murine studies show that several non-professional APCs, including cancer-associated fibroblasts (CAFs) also possess this capacity. Whether human CAFs are able to cross-present exogenous antigen, which molecular pathways are involved in this process and how this ultimately affects tumor-specific CD8+ T cell function is unknown., Methods: In this study, we investigated the ability of human colorectal cancer (CRC)-derived CAFs to cross-present neoantigen-derived synthetic long peptides (SLPs), corresponding to tumor-derived mutant peptides, and how this affects tumor-specific T-cell function. Processing of the SLP was studied by targeting components of the cross-presentation machinery through CRISPR/Cas9 and siRNA-mediated genetic ablation to identify the key molecules involved in fibroblast-mediated cross-presentation. Multispectral flow cytometry and killing assays were performed to study the effect of fibroblast cross-presentation on T cell function., Results: Here, we show that human CRC-derived CAFs display an enhanced capacity to cross-present neoantigen-derived SLPs when compared with normal colonic fibroblasts. Cross-presentation of antigens by fibroblasts involved the lysosomal protease cathepsin S. Cathepsin S expression by CAFs was detected in situ in human CRC tissue, was upregulated in ex vivo cultured CRC-derived CAFs and showed increased expression in normal fibroblasts after exposure to CRC-conditioned medium. Cognate interaction between CD8+ T cells and cross-presenting CAFs suppressed T cell function, reflected by decreased cytotoxicity, reduced activation (CD137) and increased exhaustion (TIM3, LAG3 and CD39) marker expression., Conclusion: These data indicate that CAFs may directly suppress tumor-specific T cell function in an antigen-dependent fashion in human CRC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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7. T cell receptor engineering of primary NK cells to therapeutically target tumors and tumor immune evasion.
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Morton LT, Wachsmann TLA, Meeuwsen MH, Wouters AK, Remst DFG, van Loenen MM, Falkenburg JHF, and Heemskerk MHM
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- Histocompatibility Antigens Class I, Humans, Killer Cells, Natural, Receptors, Antigen, T-Cell genetics, Multiple Myeloma, Tumor Escape
- 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-B*07:02 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-B*07:02+ 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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8. A broad and systematic approach to identify B cell malignancy-targeting TCRs for multi-antigen-based T cell therapy.
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Meeuwsen MH, Wouters AK, Jahn L, Hagedoorn RS, Kester MGD, Remst DFG, Morton LT, van der Steen DM, Kweekel C, de Ru AH, Griffioen M, van Veelen PA, Falkenburg JHF, and Heemskerk MHM
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- CD8-Positive T-Lymphocytes, Cell- and Tissue-Based Therapy, Humans, Immunotherapy, Adoptive methods, Neoplasms therapy, Receptors, Antigen, T-Cell metabolism
- Abstract
CAR T cell therapy has shown great promise for the treatment of B cell malignancies. However, antigen-negative escape variants often cause disease relapse, necessitating the development of multi-antigen-targeting approaches. We propose that a T cell receptor (TCR)-based strategy would increase the number of potential antigenic targets, as peptides from both intracellular and extracellular proteins can be recognized. Here, we aimed to isolate a broad range of promising TCRs targeting multiple antigens for treatment of B cell malignancies. As a first step, 28 target genes for B cell malignancies were selected based on gene expression profiles. Twenty target peptides presented in human leukocyte antigen (HLA)-A∗01:01, -A∗24:02, -B∗08:01, or -B∗35:01 were identified from the immunopeptidome of B cell malignancies and used to form peptide-HLA (pHLA)-tetramers for T cell isolation. Target-peptide-specific CD8 T cells were isolated from HLA-mismatched healthy donors and subjected to a stringent stepwise selection procedure to ensure potency and eliminate cross-reactivity. In total, five T cell clones specific for FCRL5 in HLA-A∗01:01, VPREB3 in HLA-A∗24:02, and BOB1 in HLA-B∗35:01 recognized B cell malignancies. For all three specificities, TCR gene transfer into CD8 T cells resulted in cytokine production and efficient killing of multiple B cell malignancies. In conclusion, using this systematic approach we successfully identified three promising TCRs for T cell therapy against B cell malignancies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
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- 2022
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9. Comparing CAR and TCR engineered T cell performance as a function of tumor cell exposure.
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Wachsmann TLA, Wouters AK, Remst DFG, Hagedoorn RS, Meeuwsen MH, van Diest E, Leusen J, Kuball J, Falkenburg JHF, and Heemskerk MHM
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- Antigens, CD20 metabolism, Humans, Immunotherapy, Adoptive methods, Receptors, Antigen, T-Cell genetics, Neoplasm Recurrence, Local, T-Lymphocytes
- 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., Competing Interests: The authors report no conflict of interest., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)
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- 2022
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10. TCR-based therapy for multiple myeloma and other B-cell malignancies targeting intracellular transcription factor BOB1.
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Jahn L, Hombrink P, Hagedoorn RS, Kester MG, van der Steen DM, Rodriguez T, Pentcheva-Hoang T, de Ru AH, Schoonakker MP, Meeuwsen MH, Griffioen M, van Veelen PA, Falkenburg JH, and Heemskerk MH
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- Animals, Cell Line, Tumor, Flow Cytometry, Genetic Engineering methods, Humans, Mice, T-Lymphocytes immunology, Xenograft Model Antitumor Assays, Immunotherapy, Adoptive methods, Lymphoma, Non-Hodgkin immunology, Multiple Myeloma immunology, Receptors, Antigen, T-Cell immunology, Trans-Activators antagonists & inhibitors
- Abstract
Immunotherapy for hematological malignancies or solid tumors by administration of monoclonal antibodies or T cells engineered to express chimeric antigen receptors or T-cell receptors (TCRs) has demonstrated clinical efficacy. However, antigen-loss tumor escape variants and the absence of currently targeted antigens on several malignancies hamper the widespread application of immunotherapy. We have isolated a TCR targeting a peptide of the intracellular B cell-specific transcription factor BOB1 presented in the context of HLA-B*07:02. TCR gene transfer installed BOB1 specificity and reactivity onto recipient T cells. TCR-transduced T cells efficiently lysed primary B-cell leukemia, mantle cell lymphoma, and multiple myeloma in vitro. We also observed recognition and lysis of healthy BOB1-expressing B cells. In addition, strong BOB1-specific proliferation could be demonstrated for TCR-modified T cells upon antigen encounter. Furthermore, clear in vivo antitumor reactivity was observed of BOB1-specific TCR-engineered T cells in a xenograft mouse model of established multiple myeloma. Absence of reactivity toward a broad panel of BOB1
- but HLA-B*07:02+ nonhematopoietic and hematopoietic cells indicated no off-target toxicity. Therefore, administration of BOB1-specific TCR-engineered T cells may provide novel cellular treatment options to patients with B-cell malignancies, including multiple myeloma., (© 2017 by The American Society of Hematology.)- Published
- 2017
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