Particulate based vaccines for cancer immunotherapy

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