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Your search keyword '"Maj de Rooij"' showing total 5 results
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5 results on '"Maj de Rooij"'

1. 10.04 A library of novel cancer testis specific T-cell receptors for T-cell receptor gene therapy

Author

Jhf Falkenburg, Eme Verdegaal, PA van Veelen, M.G.D. Kester, D Remst, Maj de Rooij, M.H.M. Heemskerk, A Wouters, RS Hagedoorn, and DM Steen

Subjects
T-Cell Receptor Gene, Genetic enhancement, T-cell receptor, Cancer research, medicine, Cancer, chemical and pharmacologic phenomena, Avidity, Context (language use), Human leukocyte antigen, Biology, medicine.disease, CD8
Abstract

Background The positive clinical effect of T-cell receptor(TCR) gene therapy on tumor regression has previously been demonstrated by NY-ESO-1 TCR-gene therapy. To seriously increase the number of cancer patients that can be treated with TCR-gene therapy we aim to identify a novel set of high-affinity Cancer Testis (CT) specific TCRs targeting different CT-antigens in a variety of prevalent HLA-class I alleles. Materials and Methods In this study, we selected by bioinformatic tools the most promising CT-genes to target, and from these genes we identified by HLA-peptidomics the naturally processed and presented HLA-class I peptides. With these peptides HLA-tetramers were generated, and by MACS enrichment and single cell sorting CT-specific CD8+ T-cell clones were selected from the allo-HLA repertoire of healthy donors. By performing several different functional assays the high function avidity CT-clones with a safe recognition pattern were selected. To evaluate the potential for clinical application in TCR-gene therapy, TCRs were sequenced, and transferred into peripheral blood derived CD8+ T cells. Results In total we identified, 7 novel CT-specific TCRs that effectively target MAGE-A1, MAGE-A3, MAGE-A6 and MAGE-A9 expressing tumors cells in the context of HLA-A1, -A2, -A3, -B7, -C7 and -B35. Conclusions With this set of 7 novel CT-specific TCRs we expand the arsenal of tumor specific TCRs. With this expanding library of TCRs it would be possible to select in future for each cancer patient, based on HLA typing and gene expression, a useful TCR to generate a personalized TCR-gene therapy products. In addition, patients could be treated with multiple TCRs to enhance the efficacy and increase the durability of clinical responses by reducing the likelihood of tumor escape. Disclosure Information M.A.J. de Rooij: None. D.M. Steen: None. D. Remst: None. A. Wouters: None. M.G.D. Kester: None. R.S. Hagedoorn: None. P.A. van Veelen: None. E.M.E. Verdegaal: None. J.H.F. Falkenburg: None. M.H.M. Heemskerk: None.

Published
2021

2. P07.02 High-affinity TCRs specific for cancer testis antigens as a therapy for multiple myeloma and solid tumors

Author

M.H.M. Heemskerk, Fjh Falkenburg, M.G.D. Kester, Maj de Rooij, A Wouters, RS Hagedoorn, D Remst, M. van der Meent, DM van der Steen, and PA van Veelen

Subjects
Negative selection, T-cell receptor, medicine, Cancer research, Cancer/testis antigens, Myeloid leukemia, Context (language use), Human leukocyte antigen, Biology, medicine.disease, Multiple myeloma, CD8
Abstract

Background Cancer Testis Antigens (CTAs) are highly expressed in multiple different tumor types, but silent in normal tissue, except the testis. This tumor-restricted expression pattern makes them an ideal target for adoptive T-cell therapy. However, the responsiveness in clinical setting may be hampered because high-affinity T cells against self-antigens presented in the context of self-HLA are deleted in the thymus by negative selection. In this study, we aim to identify high-affinity T cell receptors (TCRs) specific for CTAs from the allogeneic-HLA repertoire. Materials and Methods In this study, HLA class I binding peptides derived from different CTA genes were identified by HLA-peptide elution experiments and subsequent mass spectrometric analysis. From the identified peptides HLA tetramers were generated to isolate peptide specific CD8+ T cells from healthy allogeneic donors. Efficacy and safety of the TCRs was determined by various different stimulation assays. The most potent TCRs were sequenced, analyzed and transduced into peripheral CD8+ and CD4+ T cells to confirm CTA specific cytokine production and cytotoxicity. Results MAGE and CTAG peptides were eluted from multiple myelomas, EBV-transformed lymphoblastic cells, acute myeloid leukemia and ovarium carcinomas. We selected TCRs recognizing 3 different MAGE-A1 peptides in the context of HLA-A*02:01, HLA-A*03:01 and HLA-B*07:02. Furthermore, we selected TCRs specific for MAGE-A3 in the context of HLA-B*35:01 and HLA-A*01:01; TCRs specific for MAGE-A9 in the context of HLA-A*01:01 and TCRs specific for CTAG1 in the context of HLA-A*02:01. The selected T-cell clones demonstrated efficient recognition of MAGE-A1, MAGE-A3 or CTAG1 positive multiple myeloma and solid tumor cell lines without detectable cross-reactivity. Conclusions We identified multiple different TCRs from the allogeneic-HLA repertoire specific for CTA genes. These TCRs demonstrate efficient recognition and killing of CTA positive multiple myeloma and solid tumor cell lines and did not show any cross-reactivity. The peptides recognized by the TCRs are presented in different HLA alleles. Since, 71% of the world population contains one of these HLA-alleles, a large percentage suffering from a MAGE or CTAG positive tumor could potentially be treated with the identified TCRs by TCR-gene therapy. Disclosure Information M.A.J. de Rooij: None. D.M. van der Steen: None. D. Remst: None. A. Wouters: None. M. van der Meent: None. R.S. Hagedoorn: None. M.G.D. Kester: None. P.A. van Veelen: None. F.J.H. Falkenburg: None. M.H.M. Heemskerk: None.

Published
2020

4. A library of cancer testis specific T cell receptors for T cell receptor gene therapy.

Author

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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5. Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers.

Author

Scheper W, Kelderman S, Fanchi LF, Linnemann C, Bendle G, de Rooij MAJ, Hirt C, Mezzadra R, Slagter M, Dijkstra K, Kluin RJC, Snaebjornsson P, Milne K, Nelson BH, Zijlmans H, Kenter G, Voest EE, Haanen JBAG, and Schumacher TN

Subjects
CD8-Positive T-Lymphocytes immunology, Humans, Jurkat Cells, Lymphocytes, Tumor-Infiltrating immunology, Phenotype, Reproducibility of Results, Neoplasms immunology, Neoplasms pathology, Receptors, Antigen, T-Cell metabolism
Abstract

Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites 1 . However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor reactivity of the intratumoral TCR repertoire of CD8 + T cells in ovarian and colorectal cancer-two tumor types for which T cell infiltrates form a positive prognostic marker 2,3 . Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8 + T cells. Furthermore, in two of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire.

Published
2019
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