Rational vaccine designs against cancer

Welwyn Garden City, Hertfordshire
Tuesday, 16 October 2007

Rational vaccine designs against cancer

Rational vaccine designs against cancer
Tuesday, 16 October 2007 09:00 - 17:00

BioPark Hertfordshire
Broadwater Road
Welwyn Garden City
United Kingdom

Map and Directions

The goal of the meeting is to bring together experts to discuss concepts and to exchange data in the field of vaccination against cancer. The focus will be on rational design of vaccines aimed to induce immunity against molecularly defined antigens where immune outcome and efficacy can be measured. Topics will include the nature of antigenic targets, the design and delivery of vaccines, and objective methods to measure responses in patients. Pre-clinical models will be included to address immunological principles relevant to overcoming tolerance and to activating selected immune effector pathways. Therapeutic vaccination against persistent infections will be discussed in parallel, presenting clear opportunities for virologists and immunologists to exchange data and experience. Clinical trials are the key and data from vaccination of normal adults and patients with cancer will be presented. In addition to expert speakers, time for detailed discussion will be included. Knowledge of the immune response together with gene-based vaccine designs can now be used to direct the powerful immune effectors against target molecules. Sharing of information on this rapidly developing area relevant to human cancer is the object of this conference.

Meetings Chair: Prof Freda Stevenson, University of Southampton


9:00 – 9:45 Registration

9:45 – 10:00 Introduction by the Chair: Professor Freda Stevenson, University of Southampton, UK

10:00 – 10:30 Developing DNA fusion vaccines to induce specific cytotoxic T lymphocyte responses against tumour antigens

Dr Jason Rice, University of Southampton, UK

The majority of known human tumour-associated antigens derive from non-mutated self-proteins. T-cell tolerance, essential to prevent autoimmunity, must therefore be cautiously overcome to generate CTL responses against these targets. We have explored DNA fusion vaccines as a strategy to induce CTL responses to a model tumour-associated antigen (TAA). The DNA construct contained foreign sequences from tetanus toxin to induce a non-tolerant CD4 T-cell helper response, and an MHC Class I-binding tumour peptide sequence derived from the TAA. This simple strategy can engage anti-microbial T-cell help to activate polyclonal lower avidity tumour-reactive CTL from a tolerized repertoire, with no evident autoimmunity.

10:30 – 11:00 Synthetic viral nucleic acids as adjuvants for cancer immunotherapy

Dr Sandra Diebold, Guy’s Hospital, London, UK

Viral nucleic acids have been identified as potent immune stimulators triggering a variety of innate pattern recognition receptors. There are three classes of viral nucleic acids, all of which are recognised by specific Toll-like receptors upon uptake into a specialised endosomal compartment and by ubiquitously expressed cytoplasmic pattern recognition receptors inside virus infected cells. Toll-like receptor-mediated activation plays an important role in linking innate immune responses with the induction of suitable adaptive immune responses. Because of their potent adjuvant activity, synthetic mimics of viral nucleic acids are promising candidates to improve the efficacy of current protocols for tumour immunotherapy.

11:00 – 11:10 Group photo

11:10 – 11:30 Mid-morning break and Poster Viewing

11:30 – 12:00 CD8 T cell programming by members of the TNF receptor superfamily

Dr. Aymen Al-Shamkhani, University of Southampton, UK

12:00 – 12:30 Intradermal delivery of DNA vaccines: from mouse to clinical application

Dr John Haanen, NKI-AVL, Amsterdam

Two years ago we developed a novel intradermal DNA vaccine delivery strategy. This was based on in vivo antigen expression measurements using the luciferase reporter. The strategy makes use of a permanent make-up or tattoo device and is robust in terms of induction of cellular vaccine-specific immunity. The strategy that was developed in a mouse model has been successfully validated in a non-human primate model and will be tested in end-stage melanoma patients in 2007. Furthermore, models are being developed to unravel the mechanism of action of DNA tattooing using intravital imaging and a ex vivo human skin model is now available for optimizing the strategy for human skin.

12:30 – 12:50 Tour of the BioPark

12:50 – 13:50 Lunch and Poster Viewing

13:50- 14:20 Prime-boost with alternating DNA vaccines designed to engage different antigen-presentation pathways

Dr Stephen Thirdborough, Southampton University, UK

The route for presentation of antigen to CD8 or CD4 T cells following DNA vaccination is critical for determining outcome, but the pathways involved are unclear. We have generated two DNA vaccine designs aimed to elicit CD8 T-cell responses against a specific peptide-epitope either by direct- or cross-presentation. These vaccines can be combined in an alternating prime-boost regime, in either order, to generate substantially expanded memory CD8 T cells, with potent effector function. Our findings demonstrate that vaccination protocols involving different modes of antigen presentation at prime and boost can significantly improve the effectiveness of immunization

14:20 – 14:50 T cell immunity to Cancer-Testis Antigens in patients with multiple myeloma

Professor Paul Moss, University of Birmingham, UK

Cancer testis antigens are expressed in the testis and exist in an immunologically privileged site where they are not thought to induce T cell tolerance. However, expression of proteins within the CTAg family is detected in many malignant cells where they can induce cellular and humoral immunity. Within the last few years expression of several CTAg proteins has been described in malignant plasma cells isolated from patients with multiple myeloma. We have studied the CD8 and CD4 T cell immune response to CTAg in these patients and demonstrate a fluctuating pattern of immunity with disease progression. The relevance of this to immunotherapeutic approaches will be discussed

14:50 - 15:20 The polycomb group proteins, BMI-1 and EZH2, are tumour-associated antigens

Dr Jane Steele, Birmingham University, UK

We applied SEREX technology to patients with primary hepatocellular carcinoma and identified the polycomb group (PcG) protein BMI-1 which is over-expressed in a range of different tumours. Further studies identified T cell responses to both BMI-1 and another PcG protein, EZH2, in cancer patients and at relatively lower levels in some normal donors. EZH2-derived peptides can stimulate the in vitro expansion of specific T cells from peripheral blood lymphocytes, and this is enhanced when the CD25 T cell population is depleted. EZH2-specific CTL clones recognize endogenously processed EZH2 in both HLA-matched fibroblasts and tumour cell lines.

15:20 – 15:45 Afternoon Tea/Coffee and Last Poster Viewing

15:45 – 16:15 The individuality of the anti-tumor T cell repertoire in patients supports the need to individualize monitoring and therapeutic approaches

Dr Thomas Wolfel, Johannes Gutenberg University, Mainz, Germany

16:15 – 16:45 Taking DNA vaccination into the clinic

Dr Christian Ottensmeier, University of Southampton, UK

DNA vaccines are a promising strategy for inducing specific immune responses in patients. In and early phase clinical trials programme we assess whether DNA vaccines building on our preclinical work can successfully induce specific immune responses. We are using sequences from tetanus toxin, to induce strong linked T cell help for the tumour antigen of interest and to break tolerance. Early clinical trials data support that such responses can safely be induced in patients

16:40 – 17:00 Chairman’s summing up

About the speakers

Dr Jason Rice, University of Southampton, UK
Dr Rice began working in the laboratory of Prof Freda Stevenson (Southampton, UK) in 1995, at the outset of the DNA fusion vaccine project. After initially working on vaccines designed to induce antibody responses in a patient-specific manner, Dr Rice then began a project to develop a more generic DNA vaccine design, engineered to induce cytotoxic T lymphocytes against discrete peptide targets derived from tumour antigens or antigens from infectious organisms. The effectiveness of this approach is now being assessed in clinical trials.

Dr John Haanen, NKI-AVL, Amsterdam
After my medical education (Leiden University) I did my PhD study (1988-1991) at Leiden University Medical Center and DNAX, institute for biological en molecular research, Palo Alto, CA, USA on basic human Th1 studies in mycobacterial infections.
After my internist education (1991-1996), I became post-doctoral fellow at the Division of Immunology at the NKI-AVL (1997-1999) and became medical oncologist  thereafter (2001).
At the moment I run my own translational research lab on immunotherapy next to my clinical appointment as a medical oncologist at the NKI-AVL. Main research topics: DNA vaccines and adoptive cellular gene therapy.

Dr Sandra Diebold, Guy’s Hospital, London, UK
Studied Biology in Tuebingen, Germany; PhD from Free University Berlin, Germany (1999) – thesis on receptor-mediated gene transfer into dendritic cells; postdoc at CRUK LRI in Cateano Reis e Sousa’s laboratory working on viral recognition by dendritic cells (2000-2005); since beginning of 2006 prinicpal investigator at King’s College London, Guy’s Hospital, Immunobiology Department.

Dr Jane Steele, Birmingham University, UK
Senior Research Fellow, CRUK Institute for Cancer Studies, University of Birmingham
Involved with DC immunotherapy trials
Identification and characterisation of new TAA
Research Fellow Grade 2, CRUK Institute for Cancer Studies, University of Birmingham
Involved with DC immunotherapy trials
Also HPV immunology – immune responses, antigen processing and presentation
Research Fellow Grade 1A, CRC Institute for Cancer Studies, University of Birmingham
Human immune responses to HPV

Dr Christian Ottensmeier, University of Southampton, UK
Medical Degree, University of Münster, Germany 1986
MD, University of Münster, Germany 1989
Medical Training in University Hospitals of the Westfälische Wilhelmsuniversität, Münster, Germany
Research Fellow, Dpt of Turmour Immunology, Harvard, Boston to 1994
Completion of Speicalist Training, Southampton University Hospitals,
PhD, University of Southampton (Molecular Immunology) 1999
Senior Lecturer and Consultant in Medical Oncology, University of Southampton
CRUK Senior Research Fellow


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