- Lankelma Jacqueline M., Wagemakers Alex, Birnie Emma, Haak Bastiaan W., Trentelman Jos J. A., Weehuizen Tassili A. F., Ersöz Jasmin, Roelofs Joris J. T. H., Hovius Joppe W., Wiersinga W. Joost, Bins Adriaan D. Rapid DNA vaccination against Burkholderia pseudomallei flagellin by tattoo or intranasal application Virulence 2017;8 (8):1683-1694 [PubMed]
- Bins Adriaan D., Jorritsma Annelies, Wolkers Monika C., Hung Chien-Fu, Wu T.-C., Schumacher Ton N. M., Haanen John B. A. G. A rapid and potent DNA vaccination strategy defined by in vivo monitoring of antigen expression Nature medicine 2005;11 (8):899-904 [PubMed]
- Wagemakers A., Mason L. M. K., Oei A., de Wever B., van der Poll T., Bins A. D., Hovius J. W. R. Rapid outer-surface protein C DNA tattoo vaccination protects against Borrelia afzelii infection Gene therapy 2014;21 (12):1051-1057 [PubMed]
- Headley Mark B., Bins A. , Nip Alyssa, Roberts Edward W., Looney Mark R., Gerard Audrey, Krummel Matthew F. Visualization of immediate immune responses to pioneer metastatic cells in the lung Nature 2016;531 (7595):513-517 [PubMed]
- Bins Adriaan D., Wolkers Monika C., van den Boom Marly D., Haanen John B. A. G., Schumacher Ton N. M. In vivo antigen stability affects DNA vaccine immunogenicity Journal of immunology (Baltimore, Md. 2007;179 (4):2126-2133 [PubMed]
Adriaan Bins (1973) studied medicine and molecular biology (cum laude) at Leiden University and obtained a PhD degree in 2007 at the Netherlands Cancer Institute. This laid the foundation for his long standing interest in vaccination, in particular cancer vaccination. He recieved his medical training at the AMC in Amsterdam and certified in 2014 as a medical oncologist. His group focusses on novel ways to target the immune system towards cancer cells, combining preclinical and clinical approaches.
A.D. Bins MD PhD (Projects)
Veni 91610095 (2010)
Development of DNA tattoo vaccine candidates directed against Mycobacterium Tuberculosis
Intradermal DNA vaccines are able to induce strong cellular immunity. Contrary to most experimental T cell vaccines, they do not induce vector specific immunity that hinders subsequent boosts. In addition, the low production costs and long shelf-life potentially make DNA vaccines very suitable for vaccination against infectious diseases that are prevalent in developing countries, such as tuberculosis.
The minimal requirement of a DNA vaccine is that it encodes an antigen driven by a strong promoter. Additionally, certain modifications to the encoded antigen have proven to be beneficial for optimal induction of cellular immunity. In this respect the efficacy of antigen presentation is thought to be a crucial factor. With the help of a model to image cellular processes in the dermis of living mice using in vivo confocal microscopy, we have studied antigen presentation following intradermal DNA vaccination in vivo.
By imaging the antigen presentation of the modified and unmodified zsGreen fluorescent proteins, we have identiief that the mode of antigen release from keratinocytes is crucial for efficient antigen presentation. These zsGreen variants were also tested for efficacy as an intradermal DNA vaccine antigen. Hereby, this project has increased our knowledge about the immunological processes involved in DNA vaccination in general and intradermal DNA vaccination in particular.
Nanonext NNNL03D (2014)
Pigs as translational model: vaccination by tattoo with DNA in nanoparticles
Historically, mice have been used as a preclinical model for dermal vaccine development, but the results could not always be extrapolated to humans. Pig skin better resembles human skin and may therefore be a better preclinical model for human vaccine development. In this project we assessed the predictive value of a porcine dermal DNA vaccination.
Follow vaccination of 8 pigs and 5 patients with an identical HPV E6E7 DNA vaccine candidate, the T cells responses in our study in pigs were small and hard to detect, similar to the situation in humans. 2 out of 8 pigs responded, compared to 2 out of 5 patients.This is in stark contrast to C57B6 mice vaccinated with this DNA vaccine. Mice mount E7 specific T cell responses that comprise 10-40% of the CD8 T cell repertoire.
In parallel to the naked pDNA formulations used in our study, we tested formulation in HA37 polyplexes. Although this formulation showed a promising effect on the transfection efficacy, it did not augment the immunogenicity of the vaccine.
KWF 11269 (2018)
A comprehensive analysis of the feasibility of prophylactic vaccination against mismatch repair deficient cancers.
Current cancer immunotherapy with antibodies to PD-1 and CTLA-4 aims to engage an effective cytotoxic T cell response to eliminate cancer. This type of immunotherapy is called ‘checkpoint inhibition’ and has yielded promising results in several cancer types. However, it can result in life threatening auto-immune side effects as it unleashes the integral T-cell repertoire of the patient. In contrast, targeted immunotherapy (‘cancer vaccination’) stimulates only cancer-specific T cells and is therefore much less likely to cause auto-immunity. More importantly, cancer vaccines do not require tumor tissue as a source of antigen, as these are part of the vaccine. Therefore, they can induce cancer specific T-cells in healthy subjects and can be used in a preventive (‘prophylactic’) setting.
The proteins encoded by mutated genes in cancer are common targets for cancer immunotherapy as they are not present in normal tissue. These aberrant cancer proteins are referred to as neo-antigens. Most neo-antigens are so called ‘private’ antigens: they are the result of random mutagenesis and therefore are highly patient specific. Hence, they can only be identified after the tumor has emerged and cannot be predicted. This intra- and inter-tumor heterogeneity of neo-antigen expression is a major obstacle for prophylactic cancer vaccination. In this project I aim to extend my current therapeutic vaccination research to a prophylactic purpose by exploring a novel way to define neo-antigens that can be used for prophylactic cancer vaccination.
We know that some mutagenic processes result in predictable mutation patterns. This may allow for the identification of predictable, commonly occurring (so called ‘public’) neo-antigens. I intent to assess the feasibility of this novel approach for a subtype of cancers where mutagenesis is driven by a process that is very well understood, i.e. DNA mismatch repair (MMR) deficiency. For this purpose I will comprehensively analyze whether enough public neo-antigens that are both predictable and immunogenic can be identified in such cancers. As MMR deficiency (dMMR) is most prevalent among colorectal carcinoma (CRC) I will make use of samples that come out of an investigator initiated immunotherapy trial (IIT) in dMMR CRC patients, which is uniquely suited to assess the feasibility of this novel approach in a comprehensive manner.
Approximately 10-20% of all CRC are MMR deficient. Part of these dMMR CRC tumors arise in patients suffering Lynch Syndrome (LS). LS patients suffer a hereditary form of MMR deficiency that leads to an increased lifelong chance of 50 to 80% to develop cancer, particularly dMMR CRC. However, the larger part of dMMR tumors arise sporadically: 3-20% of sporadic colon, gastric , prostate , lung [3,4], ampullary , endometrial , and pancreatic cancer are dMMR.
The feature of the dMMR cancers that may result in predictable, public neo-antigen expression is their tendency to acquire deletions in stretches of repeating DNA (microsatellites). Due to this aspect of the mutation signature, these cancers often acquire frameshifts in genes that contain microsatellites (coding microsatellites, cMS). This results in out-of-frame open reading frames ('neo-ORFs') that encode potential neo-antigens, which are referred to as frameshift peptides. Contrary to most neo-antigens, frameshift peptides differ from the original protein on any amino-acid position, rather than a single position. Thus, a prophylactic cancer vaccine that targets the right frameshift peptides may target future dMMR cancers.
Using next generation sequencing (NGS) of samples obtained in the IIT we will identify frameshift peptides in each trial patient and assess the immunogenicity of each frameshift peptide. The trial provides a unique setting for this purpose, as it tests anti-PD1 treatment combined with a drug that is designed to increase the immunogenicity of frameshift peptides. In addition, we will construct cancer evolutionary trees using NGS data of additional samples of premalignant lesions (polyps) of these patients in order to identify the frameshift peptides that emerge at the earliest disease stages. Finally, we will perform IHC analyses on polyp tissues of these patients to look for features that may impede their successful immune eradication.
A. Wagemakers MD PhD
Prof. C.J.A. Punt MD PhD (Clinical and translational research in gastrointestinal cancer, with focus on colorectal cancer)
- Antonie van Leeuwenhoek Ziekenhuis
- BOOG Study Center B.V.
- Bristol-Myers Squibb Int. Corp.
- Covance Clinical and Periapproval Services SA
- KWF Kankerbestrijding
- Merck BV
- Merck Sharp & Dohme BV