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TCR's genetically linked to CD28 and CD3e do not mispair with endogous TCR chains and mediate enhanced T cell persistance and anti-melanoma activity Govers, C.C.F.M. ; Sebestyen, Z. ; Roszik, J. ; Brakel, M. van; Berrevoets, C. ; Szoor, A. ; Panoutsopoulou, K. ; Broertjes, M. ; Van, T. ; Vereb, G. ; Szollosi, J. ; Debets, R. - \ 2014
The Journal of Immunology 193 (2014)10. - ISSN 0022-1767 - p. 5315 - 5326. chimeric-antigen-receptor - gene-transfer - metastatic melanoma - cancer regression - lymphocytes - therapy - alpha - activation - toxicity - survival
Adoptive transfer of T cells that are gene engineered to express a defined TCR represents a feasible and promising therapy for patients with tumors. However, TCR gene therapy is hindered by the transient presence and effectiveness of transferred T cells, which are anticipated to be improved by adequate T cell costimulation. In this article, we report the identification and characterization of a novel two-chain TCR linked to CD28 and CD3e (i.e., TCR:28e). This modified TCR demonstrates enhanced binding of peptide–MHC and mediates enhanced T cell function following stimulation with peptide compared with wild-type TCR. Surface expression of TCR:28e depends on the transmembrane domain of CD28, whereas T cell functions depend on the intracellular domains of both CD28 and CD3e, with IL-2 production showing dependency on CD28:LCK binding. TCR:28e, but not wild-type TCR, induces detectable immune synapses in primary human T cells, and such immune synapses show significantly enhanced accumulation of TCR transgenes and markers of early TCR signaling, such as phosphorylated LCK and ERK. Importantly, TCR:28e does not show signs of off-target recognition, as evidenced by lack of TCR mispairing, as well as preserved specificity. Notably, when testing TCR:28e in immune-competent mice, we observed a drastic increase in T cell survival, which was accompanied by regression of large melanomas with limited recurrence. Our data argue that TCR transgenes that contain CD28, and, thereby, may provide T cell costimulation in an immune-suppressive environment, represent candidate receptors to treat patients with tumors.
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Magnetic-Activated Cell Sorting of TCR-engineered T cells using tCD34 as a gene marker, but not peptide-MHC multimers, results in significant numbers of functional CD4 and CD8 T cells Govers, C. ; Berrevoets, C. ; Treffers-Westerlaken, E. ; Broertjes, M. ; Debets, R. - \ 2012
Human Gene Therapy Methods 23 (2012)3. - ISSN 1946-6536 - p. 213 - 224. adoptive transfer - metastatic melanoma - cancer regression - immune-responses - lymphocytes-t - antigen - therapy - generation - receptors - requires
T cell sorting technologies with peptide-MHC multimers or antibodies against gene markers enable enrichment of antigen-specific T cells and are expected to enhance therapeutic efficacy of clinical T cell therapy. However, a direct comparison between sorting reagents for their ability to enrich T cells is lacking. Here, we compared the in vitro properties of primary human T cells gene-engineered with gp100280-288/HLA-A2 specific TCRaß upon Magnetic Activated Cell Sorting (MACS) with different peptide-MHC multimers or an antibody against truncated CD34 (tCD34). With respect to peptide-MHC multimers, we observed that streptamers, when compared to pentamers and tetramers, improved T cell yield as well as level and stability of enrichment of TCR-engineered T cells (> 65% of peptide-MHC-binding T cells, stable for at least 6 weeks). In agreement with these findings, streptamers, the only detachable reagent, revealed significant T cell expansion in the 1st week after MACS. Sorting TCR and tCD34 gene-engineered T cells with CD34 mAb resulted in the most significant T cell yield and enrichment of T cells (> 95% of tCD34 T cells, stable for at least 6 weeks). Notably, T cells sorted with CD34 mAb, when compared to streptamer, bind about two to three-fold less peptide-MHC but show superior antigen-specific up-regulated expression of CD107a and production of IFN¿. Multi-parameter flow cytometry revealed that CD4 T cells, uniquely present in CD34 mAb-sorted T cells, contributed to enhanced IFN¿ production. Taken together, we postulate that CD34 mAb-based sorting of gene-marked T cells has benefits towards applications of T cell therapy, especially those that require CD4 T cells.
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| Moisture content development in lap-joints of different wood species in outside exposure trials. Militz, H. ; Broertjes, M. ; Bloom, C.J. - \ 1998
In: 29th Annual meeting of the Int. Research Group on Wood Preservation, Maastricht, The Netherlands (1998) |
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| Leerbare natuur- en milieu-educatie. Lezing door A. Alblas. Alblas, A. ; Broertjes, J. ; Janssen, F. ; Waarlo, A.J. - \ 1995
In: Caring for the earth: de betekenis voor nme / de Lange, O., - p. 17 - 24. |
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| Praktijk-theorie en theorie over de ontwikkeling van betrokkenheid bij de natuur. Janssen, F.J.J.M. ; Waarlo, A.J. ; Alblas, A.H. ; Broertjes, J.J.S. - \ 1994
Pedagogische Studiën 71 (1994). - ISSN 0165-0645 - p. 200 - 208. |
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| Praktisches Wissen und theoretische Erkenntnisse über Lernprozesse im Bereich der Natur- und Umweltbildung. Janssen, F. ; Waarlo, A.J. ; Alblas, A. ; Broertjes, J. - \ 1993
In: Umweltbildung und Schulreform / Stokking, K., Ilien, A., Univ. Hannover (Fachbereich Erziehungswissenschaften 1) - p. 170 - 193. |
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| Praktijkkennis van leraren over natuur- en milieu-educatieve leerprocessen. Alblas, A.H. ; Broertjes, J. ; Janssen, F.J.J.M. ; Waarlo, A.J.W. - \ 1993
In: Proc. Onderwijsresearchdagen, H. van Berkel et al. (red.). Bohn Stafleu Van Loghum, Houten/Zaventem (1993) 107 |
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| Begrip en betrokkenheid. Bouwstenen voor leerbare thema's in natuur- en milieu-educatie. Alblas, A.H. ; Broertjes, J.J.S. ; Janssen, F.J.J.M. ; Waarlo, A.J. - \ 1993
Wageningen [etc.] : Vakgroep Agrarische Onderwijskunde, Landbouwuniversiteit Wageningen [etc.] - ISBN 9789067542944 - 104 p. |
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| Obituary Cornelis Broertjes (1924-1991). Harten, A.M. van - \ 1992
Mutation Breeding Newsletter 39 (1992)1/2. |
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| The present state of mutation breeding in vegetatively propagated crops. Harten, A.M. ; Broertjes, C. - \ 1991
In: Advances in plant breeding, Vol. 1 / Mandal, A.K., - p. 221 - 227. |
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| Induced mutations in vegetatively propagated crops. Harten, A.M. van; Broertjes, C. - \ 1989
In: Plant breeding reviews 6 / Janick, J., - p. 55 - 90. |
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| Applied mutation breeding for vegetatively propagated crops. Broertjes, C. ; Harten, A.M. van - \ 1988
Amsterdam : Elsevier (Developments in crop science 12) - ISBN 9780444427861 - 345 mutaties - plantenveredeling - vegetatieve vermeerdering - mutations - plant breeding - vegetative propagation
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| Application of mutation breeding methods to vegetatively propagated plants. Broertjes, C. ; Harten, A.M. van - \ 1987
In: Improving vegetatively propagated crops / Abbott, A.J., Atkin, R.K., London : Academic Press - p. 335 - 348. |
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| Sporten, mutanten en somaklonale varianten. Broertjes, C. ; Harten, A.M. van - \ 1986
Vakblad voor de Bloemisterij 44 (1986). - ISSN 0042-2223 - p. 61 - 61. |
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| Mutation breeding: a stepping-stone between Gregor Mendel and genetic manipulation (a treatise for vegetatively propagated crops). Harten, A.M. van; Broertjes, C. - \ 1986
In: Genetic manipulation in plant breeding : proceedings international symposium organized by Eucarpia, september 8 - 13, 1985, Berlin (West), Germany. - Berlin : Gruyter - ISBN 9783110105964 - p. 3 - 15. |
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Single cell origin of adventitious buds Broertjes, C. ; Harten, A.M. van - \ 1985
Euphytica 34 (1985). - ISSN 0014-2336 - p. 93 - 95. |
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Enige resultaten van een geohydrologisch onderzoek in het zuidelijk Peelgebied Rees Vellinga, E. van; Broertjes, J.P. - \ 1984
Wageningen : ICW (Nota / Instituut voor Cultuurtechniek en Waterhuishouding 1590) - 17 watervoerende lagen - permeabiliteit - nederland - de peel - pompproeven - aquifers - permeability - maps - de peel - pumping tests
In het zuidelijk Peelgebied wordt door een multidisciplinaire projectgroep een onderzoek verricht tot ontwikkeling van een procedure waarmee alternatieven voor het beheer van grond- en oppervlaktewater kunnen worden geanalyseerd en geëvalueerd, zowel met betrekking tot de waterkwaliteit als de -kwantiteit, in regio's waar landbouw, natuur en openbare watervoorziening belangrijke en dikwijls tegengestelde belangen hebben.
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| Verslag van een bezoek aan enkele Westduitse onderzoekinstellingen : van 17 - 20 oktober 1983 Nieuwhof, M. ; Broertjes, C. - \ 1983
Wageningen : IVT (Rapport / Instituut voor de Veredeling van Tuinbouwgewassen no. 188) proefstations - bondsrepubliek duitsland - plantenveredeling - onderzoeksinstituten - experimental stations - german federal republic - plant breeding - research institutes
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| Verslag van een reis naar Schotland en Engeland : augustus / september 1982 Broertjes, C. ; Eijk, J.P. van; Tuyl, J.M. van - \ 1982
Wageningen : I.V.T. (Rapport / Instituut voor de Veredeling van Tuinbouwgewassen no. 176) - 10 groot-brittannië - tuinbouw - plantenveredeling - plantenziekten - afwijkingen, planten - plantenziektekunde - plantenplagen - gewasbescherming - great britain - horticulture - plant breeding - plant diseases - plant disorders - plant pathology - plant pests - plant protection
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| Analysis of mitochondrial and chloroplast DNA from fertile and cytoplasmic male-sterile Petunia hybrida Kool, A.J. ; Haas, J.M. de; Marrewijk, G.A.M. van - \ 1982
In: Induced variability in plant breeding / Broertjes, C., Wageningen : Pudoc - p. 127 - 127. |
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