Particulate based vaccines for
cancer immunotherapy
Rodney Alexander Rosalia
The research presented in this thesis was performed at the Department of Immuno­
hematology and Bloodtransfusion, Clinical Pharmacy and Toxicology of the Leiden
University Medical Center and at the Leiden Academic Centre for Drug Research, Leiden,
The Netherlands.
Financial support for the publication of this thesis was provided by AZL Onderzoeks- en
Ontwikkelingskrediet Apotheek, and ISA Pharmaceuticals, Leiden, The Netherlands.
Cover design Andrew Ng, Rodney Rosalia
Layout Renate Siebes, Proefschrift.nu
Printed by Ipskamp Drukkers B.V.
ISBN 978-94-9202-6026
© 2014 R.A. Rosalia
All rights reserved. No part of this publication may be reproduced or transmitted in any
form or by any means, electronic or mechanical, including photocopy, recording, or any
information storage or retrieval system, without permission in writing from the author.
The copyright of the articles that have been accepted for publication or that already have
been published, has been transferred to the respective journals.
Cover Page
The handle http://hdl.handle.net/1887/28971 holds various files of this Leiden University
dissertation
Author: Rosalia, Rodney Alexander
Title: Particulate based vaccines for cancer immunotherapy
Issue Date: 2014-10-02
Particulate based vaccines for
cancer immunotherapy
Proefschrift
ter verkrijging van
de graad van Doctor aan de Universiteit Leiden,
op gezag van Rector Magnificus prof. mr. C.J.J.M. Stolker,
volgens besluit van het College voor Promoties
te verdedigen op dinsdag 2 oktober 2014
klokke 13.45 uur
door
Rodney Alexander Rosalia
geboren te Willemstad, Curaçao
in 1981
Promotiecommissie
Promotor Prof.dr. H-J. Guchelaar
Prof.dr. F. Ossendorp
Copromotor
Dr. J. Oostendorp
Overige leden
Prof.dr. T. de Gruijl
VUmc Amsterdam
Prof.dr. W. Hennink
UMC Utrecht
Dr. T. van Hall
Contents
Chapter 1
Introduction
7
Chapter 2
Dendritic cells process synthetic long peptides better than whole
37
protein, improving antigen presentation and T-cell activation
Chapter 3
Optimization of encapsulation of a synthetic long peptide in PLGA
71
nanoparticles: low burst release is crucial for efficient CD8+ T cell
activation
Chapter 4
Co-encapsulation of synthetic long peptide antigen and Toll like
95
receptor 2 ligand in poly-(lactic-co-glycolic-acid) particles results in
sustained MHC class I cross-presentation by dendritic cells
Chapter 5
Efficient ex vivo induction of T cells with potent anti-tumor activity
123
by protein antigen encapsulated in nanoparticles
Chapter 6
Poly-(lactic-co-glycolic-acid)-based particulate vaccines: nano-size is
153
a key parameter for dendritic cell uptake and immune activation
Chapter 7
CD40-targeted dendritic cell delivery of PLGA-nanoparticle vaccine
183
induce potent anti-tumor responses
Chapter 8
Targeting nanoparticles to CD40, DEC-205 or CD11c molecules on
213
DC for efficient CD8 T cell responses; a comparative study
+
Chapter 9
Discussion
243
Chapter 10
English summary – Nederlandse samenvatting
261
Chapter 11
Dankwoord, Acknowledgements & Palabranan di Danki vitae
273
Chapter 12
Curriculum vitae
281
Chapter 13
Publication list
283