Previous Talents Program Awardees

2007

Prof Melvin Berger, USA

Dr Berger is Professor of Pediatrics and Pathology at the Children’s Research Foundation of Cleveland. He is also Director of the Jeffrey Modell Foundation Center for Primary Immunodeficiencies at Rainbow, Babies and Children’s Hospital, Cleveland, OH.

Research proposal: ‘Subcutaneous vs. Intravenous Immune Globulin Treatment in Animal Models of Neuromuscular Disease’ (2 years).

It is not known if the high peaks achieved by large IV doses are necessary in autoimmune diseases or if near-constant elevated serum IgG levels obtained by frequent subcutaneous injections (which generally result in fewer systemic adverse events) would work equally well.

This study is investigating whether immunoglobulin given by frequent subcutaneous injections (SCIG) is as effective as equivalent intravenous doses of immunoglobulin (IGIV) in rat and mouse models of myasthenia gravis and myositis. In both models, and in the corresponding human diseases, the pathogenesis involves complement deposition induced by auto-antibodies. This is likely to be a continuous, ongoing process and thus the total amount of IgG given over time is more likely to be the main determinant of efficacy than the height of the peaks achieved by IV therapy. If the results confirm that SCIG is effective in these models, it is likely that clinical trials in the corresponding human diseases would follow directly, with the aim that, in future, patients can treat themselves at home and achieve a better quality of life.

Dr Andreas Goebel, UK

Dr Goebel is a Consultant Anesthetist and Honorary Research Associate at the UCLH Pain Clinic, London, in addition to holding a position as Honorary Research Associate at the Institute for Molecular Medicine in Oxford.

Research proposal: ‘Intravenous immunoglobulin in the treatment of primary trigeminal neuralgia refractory to carbamazepine’ (2 years).

Trigeminal neuralgia (TN) is a severe chronic facial pain syndrome. A significant proportion of patients do not benefit from pharmacotherapy, such as carbamazepine, or surgery.

The study is examining the use of IGIV for TN in patients that do not respond to standard treatments. The study hypothesis is that treatment with IGIV will relieve pain from TN better than saline control in a prospective, randomized controlled trial. The primary endpoint of the study is the length of time that patients remain in the study (total study length is 3 months). There are clear stopping rules based on patient’s pain score and, in addition, patients are free to leave the trial at any stage. Secondary endpoints of the study are pain, noted on an 11-point numeric rating scale, and patient global impression of change (PGIC) on days 4-7 after treatment. A successful trial outcome will hopefully stimulate clinical research in the efficacy of IGIV in other intractable chronic pain conditions, including neuropathic pain.

Dr Frederick Goldman, USA

Dr Goldman is Associate Professor of Pediatrics at the University Of Iowa College Of Medicine, IA. He is also Director of the Carver Hematopoietic Stem Cell Bank and the Pediatric Immune Disorders Clinics at the University of Iowa, IA.

Research proposal: ‘Immunomodulatory properties of IGIV in developing immune systems post hematopoietic stem cell transplant’ (1 year).

IGIV has been used extensively in hematopoietic stem cell transplant (HSCT) recipients, both as replacement therapy and as an immune modifier. This study is investigating the use of IGIV in patients undergoing HSCT, as these individuals are immunocompromised for a period of several months, and are thus predisposed to a variety of infections and other complications.

In particular, the study is examining the effect of IGIV on T cells. The study hypothesis is that IGIV displays an inhibitory effect on T cells, and that this effect occurs in a dose-dependent manner. Also, the study is investigating whether IGIV is associated with down-regulation of Th2 cytokine responses in IGIV-treated HSCT recipients. Information gained from this study could modify current strategies of dosing and timing of IGIV infusions in the transplant setting and perhaps even extend the use of this drug for a greater length of time following transplant. Furthermore, understanding the mechanism of action of IGIV with regards to how it interacts with the immune system could enhance its use in the setting of other diseases, including autoimmune disorders in general.

Dr Régine Mydlarski, Canada

Dr Mydlarski is Director of Immunodermatology at the Faculty of Medicine, University of Calgary. She previously served as Director of Immunodermatology at Sunnybrook & Women’s College Health Science Center, Toronto.

Research proposal: ‘A randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of intravenous immunoglobulin in the treatment of pemphigus vulgaris’ (2 years).

Pemphigus vulgaris (PV) is a potentially life-threatening autoimmune blistering disease of the skin and mucous membranes. Oral steroids (such as prednisone) and immunosuppressive drugs are currently considered the treatment of choice. However, these drugs are associated with a number of serious and dangerous side effects.

Dr Mydlarski’s study is comparing the efficacy and safety of IGIV to placebo in PV patients receiving standard therapies. In this study, patients meeting the study entry criteria have received standard therapies, in addition to being randomized to treatment with either IGIV or placebo. The primary outcome measure is the number of days required for both resolution of existing lesions and prevention of new ones. Secondary outcome measures include: the number of relapses, adverse events, quality of life measurements and costs of therapy. This randomized, double-blind, placebo-controlled trial may revolutionize the therapeutic approach to patients with this devastating immunobullous disease.

Dr Vera Bril, Canada

Dr Bril is a Professor of Medicine at the University of Toronto. She is also Division Director of Neurology.

Research proposal: ‘A randomized trial of plasma exchange compared with IGIV in the treatment of myasthenia gravis’ (2 years).

Acquired Mayasthenia Gravis (MG) is an autoimmune disease caused by antibodies against the acetylcholine receptor or muscle specific tyrosine kinase. Although immunotherapies are used widely to treat MG, each therapy has a different side effect profile, cost and availability.

This study is investigating the effectiveness of intravenous immunoglobulin (IGIV) to plasma exchange (PLEX) in a large number of patients with moderate-severe MG in a randomized study. Previously, only two small studies have compared immunomodulation with IGIV and PLEX. The primary endpoint of the study is the change in Quantitative Myasthenia Gravis Score (QMGS) from baseline to day 14 after treatment has ended. Secondary endpoints include the changes in QMGS from days 14-28, changes in subjective patient visual-analogue scale score, changes in acetylcholine receptor antibody titers and requirement for additional therapy. The study hypothesis is that both IGIV and PLEX will have comparable outcomes with different side-effect profiles. This trial could confirm which therapy is better for patients. In addition, information about response times, treatment duration and cost may be obtained.

Dr David Saperstein, USA

Co-Director Banner Good Samaritan Neuropathy Clinic and Clinical Associate Professor of Neurology, University of Arizona College of Medicine, Phoenix, AZ

Research proposal: ‘Database of suspected CIDP patients: identification and treatment responses’ (2 years).

The effectiveness of IGIV as a treatment for chronic inflammatory demyelinating polyneuropathy (CIDP) has previously been demonstrated in several placebo-controlled trials. These trials had rigorous and restrictive criteria which most CIDP patients do not meet. Currently, there are no universally accepted minimum criteria for selecting which polyneuropathy patients to treat for CIDP. Due to costs, therapy cannot be given too liberally.

The project involves the creation of a database containing patients treated for immune-mediated neuropathy but who do not meet formal criteria for CIDP. The project is utilizing data collected from patients treated with IGIV for suspected immune-mediated polyneuropathy from 10 neuromuscular centers throught the United States. Information collected consists of demographics, clinical findings, test results, and response to IGIV. On completion of the database it will be easier to assess factors that correlate with treatment response. Using multivariate regression analysis Dr Saperstein aims to create a predictive model. In the future this will generate the key data needed to plan a prospective, randomized trial.

Dr Mieko Toyoda, USA

Dr Toyoda is a Professor of Pediatrics, School of Medicine, UCLA, CA. She is also Director of Transplant Immunology Laboratory at Cedars-Sinai Medical Centre, CA.

Research proposal: ‘Development of novel assays to monitor human B-cell responses to alloantigens in patients undergoing desensitization with IVIG: relationship to antibody mediated rejection and responses to IVIG therapy’ (2 years).

Approximately 25% of IVIG-treated transplant patients experience antibody mediated allograft rejection. No tests currently exist to assess the efficacy of IVIG desensitization and distinguish patients who will do well from those who experience antibody mediated allograft rejection after transplantation.

This project is establishing tests to address the above issues. Dr Toyoda’s previous work has indicated that polyclonal B-cell activation and response against alloantigens may be the cause of antibody mediated rejection (AMR) in highly sensitized patients. The detection of B-cell activation could predict the risk of rejection. The study hypothesizes that abatement of B-cell activation is essential for successful transplantation in highly sensitized patients. The study is therefore investigating B-cell responses using intracellular cytokine flow cytometry (CFC) from the blood obtained pre- and post-IVIG treatment after kidney transplantation. The primary endpoint is whether alloantigen-specific B-cell responses correlate with transplantation rate, AMR and graft survival. If results confirm the hypothesis, B-cell CFC negative patients will have successful transplantations, and those who are positive are unlikely to receive transplantation and develop AMR if transplanted.