Immunology research at Medicine spans several academic units and draws on an appreciation of the underlying immunological causes of disease. The vaccines and immunotherapy theme seeks to take advantage of this immunological knowledge and to design, characterise and translate new therapies into improved clinical practice.
The therapies seek to treat diseases spanning oncology, respiratory medicine and allergy, dermatology, gastroenterology, haematology, infectious disease, neurobiology and nutrition. Importantly, strong links to clinical immunology in these areas supports our translational goals in leading to improved clinical practice.
A plethora of different approaches (both passive, not requiring de novo immune responses, or active) can be taken towards this goal as summarised in the figure at the side of the page and many of these are being explored in Southampton.
The current areas of activity can be represented as follows
:
Antibody therapeutics
(
Professors
Martin Glennie
,
Peter Johnson
,
Aymen Al-Shamkhani
and
Mark Cragg
,
Drs
Juliet Gray
,
Stephen Beers
,
Sean Lim
,
Sarah Buchan
, Ann White
and
Andrew Davies
)
Targeted radiotherapy
(
Kim Orchard
)
DNA vaccines
(
Professors
Freda Stevenson
and
Christian Ottensmeier
,
Drs
Surinder Sahota
,
Stephen Thirdborough
and
Natalia Savelyeva
)
Immune monitoring of responses after vaccination
(
Dr Gianfranco Di Genova
)
Nutritional interventions
(
Prof Phillip Calder
)
Immunotherapy using allogeneic dendritic cells
(
Prof Christian Ottensmeier
and
Dr Simon Crabb
)
Developing vaccines to infectious diseases
(
Dr Stuart Clarke
and
Dr Saul Faust
)
Immunotherapy to prevent asthma and allergies
(Professors
Hasan Arshad
,
Graham Roberts
and
Ratko Djukanovic
, and
Dr. Ramesh Kurukulaaratchy
)
Immunotherapy for neurodegenerative diseases
(
Delphine Boche
,
Clive Holmes
and
James Nicoll
)
Professors Martin Glennie , Peter Johnson , Aymen Al-Shamkhani and Mark Cragg along with Drs Juliet Gray , Stephen Beers , Sean Lim , Sarah Buchan Ann White and Andrew Davies lead the group's research into the use of monoclonal antibodies and tumour necrosis factor-like molecules to target cancer. These reagents fall into two categories - those that directly target the tumour and those that stimulate the immune system to attack it; so-called immunomodulatory mAb. Examples of the former include herceptin, cetuximab and rituximab and the group are interested in dissecting their efficacy, modes of action and ways to augment them through an integrated approach using novel mouse models, primary tumour material and access to clinical trail samples through close collaboration with pathologists ( Dr Meg Ashton-Key ), oncologists ( Prof Peter Johnson and Dr Andrew Davies ) and surgeons ( Mr Ramsey Cutress ). Examples of the immunomodulatory mAb include anti-CD40, -4IBB and -OX40 mAb and Professors Martin Glennie and Aymen Al-Shamkhani have a CR UK programme to develop novel reagents of this class into the clinic. Such agents will be used to boost cancer vaccines, or to promote ongoing, but ineffectual anti-tumor T-cell responses as well as overcome suppression by regulatory T cells. Prof Al-Shamkhani , alongside Dr Buchan , has a further active interest in developing agents that ameliorate inflammation but avoid blanket immunosuppression for the treatment of graft versus host disease and inflammatory bowel disease.
Dr Kim Orchard and The Targeted radiotherapy group are investigating radiolabelled antibodies for their ability to target haematological malignancies and improve response rates but without increasing the toxic side effects associated with chemotherapy or external beam radiotherapy. Southampton has been one of the few centres in the UK to be able to deliver this form of translational research, drawing together expertise in haematology and oncology, nuclear medicine, radiopharmacy and medical physics. Laboratory based research has rapidly lead to the development of early phase clinical trials in applying radiolabelled antibodies to haematological malignancies. For example, a phase I trial in stem cell transplantation has shown excellent bone marrow targeting, the delivery of a high radiation dose to sites of disease but with no additional toxicity.
A parallel programme of research is also ongoing into the development and use of DNA vaccines in cancer therapy. The aim is to develop vaccination strategies that induce immunity against cancer cells, thereby providing effective clinical benefit to patients. To achieve this, strategies must overcome immune tolerance and regulation, with the resulting immune effector cells able to recognise and destroy tumour cells on an ongoing basis. These programmes led by Professors Freda Stevenson and Christian Ottensmeier and Drs Surinder Sahota , Stephen Thirdborough and Natalia Savelyeva are focussed largely upon using vaccine constructs containing fragments of immunostimulatory toxins such as that from tetanus. Application of these novel vaccine designs to antigens expressed by various cancers, for example in multiple myeloma ( Surinder Sahota ) and through novel plant derived vaccines), with clinical application via collaboration with Prof Christian Ottensmeier . Their ongoing research involves investigating new approaches to increase vaccine efficacy, including novel vaccine designs, the co-delivery of immune adjuvants or immune modulating agents, and physical delivery methods.
Dr Gianfranco Di Genova is working on a related aspect of vaccination and is interested in determining the importance of bystander activation of CD4+ T helper memory cells following conventional protein vaccination in humans. In addition, he is developing mouse models and other tools to dissect the underlying mechanisms involved in the maintenance of immunological memory.
Alternative cellular immunotherapy approaches are being investigated by Professor Christian Ottensmeier and Dr Simon Crabb who are investigating the potential of allogeneic dendritic cells (ADCs). Currently they are assessing the safety of ADCs pulsed with LAMP-hTERT mRNA in HLA-A2+ patients with prostate cancer. Although focused predominantly on cancer, research findings in this area are also be applicable to infectious disease and veterinary medicine.
In a separate facet of the theme, Professor Philip Calder in Medicine is performing novel studies looking at the impact of nutritional interventions on immune response in humans, using antibody response to seasonal influenza vaccination as the primary outcome.
In a related branch of vaccine research,
Dr Stuart Clarke
has a major interest in developing vaccines to infectious diseases. He works mostly with Streptococcus pneumoniae, but also Neisseria meningitidis, Haemophilus influenzae and Staphylococcus aureus. Alongside
Dr Clarke
,
Dr Saul Faust
leads the paediatric clinical component of longitudinal molecular epidemiological bacterial carriage studies relating to vaccine policy and design. In addition, Dr Faust is director of the Southampton Wellcome Trust Clinical Research Facility (
SWTCRF
) - one of the main academic paediatric vaccine centres that form the UK Paediatric Vaccine Group. In collaboration with colleagues at Oxford, Bristol, St Georges London and the Health Protection Agency the SWTCRF design and deliver multi-centre trials in paediatric and adult vaccine research. They have previously investigated paediatric head-to-head trials of pandemic vaccines and undertaken subsequent studies to assess their persistence and immunogenicity.
Dr Faust
also collaborates with the Oxford Jenner Institute to enroll Southampton adults into early phase trials of novel vaccines against influenza and malaria.
In an alternative approach to disease intervention, Professors
Hasan Arshad
,
Graham Roberts
,
Ratko Djukanovich
, and
Dr. Ramesh
within the
Respiratory Biomedical Research Unit
and with funding from the
National Institute of Health Research
, are investigating ways to prevent asthma and allergies. For example, in their Mite allergen Prevention Study, high doses of dust mite allergen are being administered sublingually during very specific times during early childhood in order to induce oral tolerance and block the development of airway inflammation and asthma. It is hoped that this will infer life-long protection against the development of allergy in healthy infants who are at a high risk of asthma and allergy.
Other groups within Medicine are interested in Immunotherapy for Alzheimer's disease (AD). Delphine Boche , Clive Holmes and James Nicoll are interested in the abnormal aggregation of amyloid-β and have shown that Aβ immunisation, both active and passive, in transgenic mouse models of AD has resulted in Aβ plaque removal with functional benefits. A subsequent clinical study in humans resulted in changes to the AD process with evidence of amyloid-β removal, although some unwanted side effects were observed. However, if these can be surmounted, a similar approach could be used for other neurodegenerative diseases in which abnormal accumulation of a protein occurs in the CNS.
Alternative approaches to immumotherapy and vaccination. Modified from Gray et al, Pediatr Blood Cancer 2009