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Designing T-cells with desired T-cell receptor make-up for immunotherapy
Proefschrift ter verkrijging van
de graad van Doctor aan de Universiteit Leiden, op gezag van Rector Magnificus prof.mr. P.F. van der Heijden,
volgens besluit van het College voor Promoties te verdedigen op woensdag 20 april 2011
klokke 15:00 uur
door Margaretha Magdalena van Loenen geboren te Oss in 1980
2
Prof.dr. H.J Stauss, University College London
FINANCIAL SUPPORT
The work described in this thesis was financially supported by the Dutch Cancer Society (KWF). Printing of this thesis was financially supported by the Dutch Cancer Society, J.E. Jurriaanse Stichting, BD Biosciences, Beckman Coulter, and Lonza.
COLOFON
Published material in chapters 2, 3, 4 and 5 was reprinted with per- mission from their respective publishers.
© M.M. van Loenen, 2011
Cover design and layout by J. Folmer
Printed in the Netherlands by Ipskamp Drukkers B.V.
Designing T-cells with desired T-cell receptor make-up for immunotherapy
Contents
1. INTRODUCTION 7
Stem cell transplantation 7
Donor lymphocyte infusion / T-cell based im-
munotherapy 8
T-cells 9
T-cell differentiation 11
Gene therapy 14
2. RAPID RE-EXPRESSION OF RETROVIRALLY INTRODUCED VERSUS ENDOGENOUS TCRS IN ENGINEERED T-CELLS AFTER ANTIGEN- SPECIFIC STIMULATION 23
Abstract 23
Introduction 24
Results 25
Discussion 30
Materials and Methods 33
Acknowledgements 35
3. KINETIC PRESERVATION OF DUAL-SPECI- FICITY OF COPROGRAMMED MINOR HIS- TOCOMPATIBILITY ANTIGEN-REACTIVE VIRUS-SPECIFIC T-CELLS 37
Abstract 37
Introduction 38
Materials and Methods 39
Results 41
Discussion 46
4. MIXED TCR DIMERS HARBOR POTENTIAL- LY HARMFUL NEOREACTIVITY 49
Abstract 49
Introduction 50
Results 51
Discussion 56
Materials and Methods 59
Acknowledgements 61
Supporting information 62
5. OPTIMIZATION OF THE HA-1-SPECIFIC T-CELL RECEPTOR FOR GENE THERAPY OF HEMATOLOGICAL MALIGNANCIES 67
Abstract 67
Introduction 68
Design and methods 69
Results 71
Discussion 79
Authorship and disclosures 81
6. SUMMARY AND DISCUSSION 83
Summary 83
General discussion 86
Characteristics of the introduced TCR 86 Specificity of the endogenous TCR 90
Clinical study 94
7. NEDERLANDSE SAMENVATTING 97
Achtergrond 97
Dit proefschrift 99
Klinische studie 103
8. NAWOORD 105
9. CURRICULUM VITAE 107
List of publications 109
10. REFERENCES 111
