Jackie de Belin
Oxford BioMedica
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Featured researches published by Jackie de Belin.
Clinical Cancer Research | 2010
Robert J. Amato; Robert E. Hawkins; Howard L. Kaufman; John A. Thompson; Piotr Tomczak; Cezary Szczylik; Mike McDonald; Sarah Eastty; William Shingler; Jackie de Belin; Madusha Goonewardena; Stuart Naylor; Richard Harrop
Purpose: The TroVax Renal Immunotherapy Survival Trial was a randomized, placebo-controlled phase III study that investigated whether modified vaccinia Ankara encoding the tumor antigen 5T4 (MVA-5T4) prolonged survival of patients receiving first-line standard-of-care (SOC) treatment for metastatic renal cell cancer. Experimental Design: Patients with metastatic clear cell renal cancer, prior nephrectomy, and good or intermediate prognosis were randomized 1:1 to receive up to 13 immunizations of MVA-5T4/placebo in combination with either sunitinib, interleukin-2 or interferon-α. The primary end point was overall survival. Secondary end points included progression-free survival, overall response rate, and safety. Results: Seven hundred thirty-three patients were recruited (365 MVA-5T4 and 368 placebo). Treatment arms were well balanced for SOC and prognosis. No significant difference in the incidence of adverse events or serious adverse events was observed. No significant difference in overall survival was evident in the two treatment arms (median 20.1 months MVA-5T4 versus 19.2 months placebo; P = 0.55). The magnitude of the 5T4-specific antibody response induced by vaccination with MVA-5T4 was associated with enhanced patient survival. Furthermore, exploratory analyses suggested a number of pretreatment hematologic factors that could identify patients who derive significant benefit from this vaccine. Conclusion: MVA-5T4 in combination with SOC was well tolerated, but no difference in survival was observed in the overall study population. Exploratory analyses indicate that there may be subsets of patients who could gain significant benefit from MVA-5T4, but such results would need to be confirmed in future randomized clinical studies. Clin Cancer Res; 16(22); 5539–47. ©2010 AACR.
Investigative Ophthalmology & Visual Science | 2013
Katie Binley; Peter Widdowson; Julie Loader; Michelle Kelleher; Sharifah Iqball; Georgina Ferrige; Jackie de Belin; Marie Carlucci; Diana Angell-Manning; Felicity Hurst; Scott Ellis; James Miskin; Alcides Fernandes; Paul Wong; Rando Allikmets; C. Bergstrom; Thomas M. Aaberg; Jiong Yan; Jian Kong; Peter Gouras; Annick Prefontaine; Mark Vezina; Martin Bussieres; Stuart Naylor; Kyriacos Mitrophanous
PURPOSE StarGen is an equine infectious anemia virus (EIAV)-based lentiviral vector that expresses the photoreceptor-specific adenosine triphosphate (ATP)-binding cassette transporter (ABCA4) protein that is mutated in Stargardt disease (STGD1), a juvenile macular dystrophy. EIAV vectors are able to efficiently transduce rod and cone photoreceptors in addition to retinal pigment epithelium in the adult macaque and rabbit retina following subretinal delivery. The safety and biodistribution of StarGen following subretinal delivery in macaques and rabbits was assessed. METHODS Regular ophthalmic examinations, IOP measurements, ERG responses, and histopathology were carried out in both species to compare control and vector-treated eyes. Tissue and fluid samples were obtained to evaluate the persistence, biodistribution, and shedding of the vector following subretinal delivery. RESULTS Ophthalmic examinations revealed a slightly higher level of inflammation in StarGen compared with control treated eyes in both species. However, inflammation was transient and no overt toxicity was observed in StarGen treated eyes and there were no abnormal clinical findings. There was no StarGen-associated rise in IOP or abnormal ERG response in either rabbits or macaques. Histopathologic examination of the eyes did not reveal any detrimental changes resulting from subretinal administration of StarGen. Although antibodies to StarGen vector components were detected in rabbit but not macaque serum, this immunologic response did not result in any long-term toxicity. Biodistribution analysis demonstrated that the StarGen vector was restricted to the ocular compartment. CONCLUSIONS In summary, these studies demonstrate StarGen to be well tolerated and localized following subretinal administration.
Journal of Immunotherapy | 2009
Robert J. Amato; William Shingler; Madusha Goonewardena; Jackie de Belin; Stuart Naylor; Jaroslaw Jac; James Willis; Somyata Saxena; Joan Hernandez-McClain; Richard Harrop
Attenuated vaccinia virus, modified vaccinia Ankara (MVA) has been engineered to deliver the tumor antigen 5T4 (TroVax). MVA-5T4 has been evaluated in an open-label phase 2 trial in metastatic renal cell cancer patients in which the vaccine was administered alone or in combination with interferon-α-2b (IFN-α). The safety, immunologic, and clinical efficacy of MVA-5T4 with or without IFN-α was determined. Twenty-eight patients with metastatic renal cell cancer were treated with MVA-5T4 alone (13) or plus IFN-α (15). The 5T4-specific cellular and humoral responses were monitored throughout the study. Clinical responses were assessed by measuring changes in tumor burden by computed tomography or magnetic resonance imaging scan. MVA-5T4 was well tolerated with no serious adverse event attributed to vaccination. Of 23 intent-to-treat patients tested for immune responses postvaccination, 22 (96%) mounted 5T4-specific antibody and/or cellular responses. One patient treated with MVA-5T4 plus IFN-α showed a partial response for >7 months, whereas an additional 14 patients (7 receiving MVA-5T4 plus IFN and 7 receiving MVA-5T4 alone) showed periods of disease stabilization ranging from 1.73 to 9.60 months. Median progression free survival and overall survival for all intent-to-treat patients was 3.8 months (range: 1 to 11.47 mo) and 12.1 months (range: 1 to 27 mo), respectively. MVA-5T4 administered alone or in combination with IFN-α was well tolerated in all patients. Despite the high frequency of 5T4-specific immune responses, it is not possible to conclude that patients are receiving clinical benefit. The results are encouraging and warrant further investigation.
Journal of Immunotherapy | 2010
Richard Harrop; William Shingler; Michelle Kelleher; Jackie de Belin; Peter Treasure
The attenuated vaccinia virus MVA has been engineered to deliver the tumor antigen 5T4 (MVA-5T4; TroVax), a surface glycoprotein expressed by most solid tumors. MVA-5T4 has been tested in 2 phase I/II and 7 phase II clinical trials in colorectal (4 trials), renal (4 trials), and prostate (1 trial) advanced cancer patients. Data have been collated from all 9 studies and used to investigate the magnitude and kinetics of 5T4-specific antibody responses after vaccination and to identify potential associations between the immune response and patient survival. Antibody responses specific for the 5T4 tumor antigen and the MVA viral vector were quantified in plasma samples taken from cancer patients before and after the treatment with MVA-5T4. Immunologic and survival data were analyzed using proportional hazards regression adjusting for age and gender. Both survival and immunologic response data were available for 189 patients with colorectal (n=73), renal (n=89), and prostate (n=27) cancer. Before the treatment with MVA-5T4, 5T4-specific antibody levels were significantly elevated in cancer patients compared with healthy donors. After MVA-5T4 administration, 5T4-specific antibody responses increased significantly and peaked after 3 to 4 vaccinations. Exploratory analyses showed significant associations between 5T4 antibody responses and overall survival across all 9 trials and in patients with colorectal cancer. The 5T4-specific antibodies were present at higher levels in cancer patients compared with healthy donors and increased significantly after treatment with MVA-5T4. Although the studies were uncontrolled, there were encouraging signs of activity which is associated with the magnitude of 5T4-specific antibody responses.
Human Gene Therapy | 2012
Katie Binley; Peter Widdowson; Michelle Kelleher; Jackie de Belin; Julie Loader; Georgina Ferrige; Marie Carlucci; Margaret Esapa; Daniel Chipchase; Diana Angell-Manning; Scott Ellis; Kyriacos Mitrophanous; James Miskin; V. Bantseev; T. Michael Nork; Paul E. Miller; Stuart Naylor
RetinoStat(®) is an equine infectious anemia virus-based lentiviral gene therapy vector that expresses the angiostatic proteins endostatin and angiostatin that is delivered via a subretinal injection for the treatment of the wet form of age-related macular degeneration. We initiated 6-month safety and biodistribution studies in two species; rhesus macaques and Dutch belted rabbits. After subretinal administration of RetinoStat the level of human endostatin and angiostatin proteins in the vitreous of treated rabbit eyes peaked at ∼1 month after dosing and remained elevated for the duration of the study. Regular ocular examinations revealed a mild to moderate transient ocular inflammation that resolved within 1 month of dosing in both species. There were no significant long-term changes in the electroretinograms or intraocular pressure measurements in either rabbits or macaques postdosing compared with the baseline reading in RetinoStat-treated eyes. Histological evaluation did not reveal any structural changes in the eye although there was an infiltration of mononuclear cells in the vitreous, retina, and choroid. No antibodies to any of the RetinoStat vector components or the transgenes could be detected in the serum from either species, and biodistribution analysis demonstrated that the RetinoStat vector was maintained within the ocular compartment. In summary, these studies found RetinoStat to be well tolerated, localized, and capable of persistent expression after subretinal delivery.
Cancer Immunology, Immunotherapy | 2011
Richard Harrop; William Shingler; Mike McDonald; Peter Treasure; Robert J. Amato; Robert E. Hawkins; Howard L. Kaufman; Jackie de Belin; Michelle Kelleher; Madusha Goonewardena; Stuart Naylor
Few immunotherapy compounds have demonstrated a direct link between the predicted mode of action of the product and benefit to the patient. Since cancer vaccines are thought to have a delayed therapeutic effect, identification of the active moiety may enable the development of an early marker of efficacy. Patients with renal cancer and requiring first-line treatment for metastatic disease were randomized 1:1 to receive MVA-5T4 (TroVax®) or placebo alongside Sunitinib, IL-2 or IFN-α in a multicentre phase III trial. Antibody responses were quantified following the 3rd and 4th vaccinations. A surrogate for 5T4 antibody response (the immune response surrogate; IRS) was constructed and then used in a survival analysis to evaluate treatment benefit. Seven hundred and thirty-three patients were randomized, and immune responses were assessed in 590 patients. A high 5T4 antibody response was associated with longer survival within the MVA–5T4-treated group. The IRS was constructed as a linear combination of pre-treatment 5T4 antibody levels, hemoglobin and hematocrit and was shown to be a significant predictor of treatment benefit in the phase III study. Importantly, the IRS was also associated with antibody response and survival in an independent dataset comprising renal, colorectal and prostate cancer patients treated with MVA–5T4 in phase I–II studies. The derivation of the IRS formed part of an exploratory, retrospective analysis; however, if confirmed in future studies, the results have important implications for the development and use of the MVA–5T4 vaccine and potentially for other similar vaccines.
Molecular Cancer Research | 2003
Paul J. Adam; Joanne Berry; Julie Loader; Kerry Louise Tyson; Graham Craggs; Paul A. Smith; Jackie de Belin; Graham Steers; Francesco Pezzella; Kris F. Sachsenmeir; Alasdair Stamps; Athula Herath; Edith Sim; Michael J. O'Hare; Adrian L. Harris; Jonathan Alexander Terrett
Cancer Immunology, Immunotherapy | 2012
Richard Harrop; Peter Treasure; Jackie de Belin; Michelle Kelleher; Gemma Bolton; Stuart Naylor; William Shingler
Investigative Ophthalmology & Visual Science | 2012
Scott Ellis; James Miskin; Katie Binley; Jackie de Belin; Julie Loader; Michelle Kelleher; Stuart Naylor; Kyriacos Mitrophanous
Investigative Ophthalmology & Visual Science | 2011
Stuart M. Naylor; Michelle Kelleher; Julie Loader; Jackie de Belin; James Miskin; Georgina Ferrige; Marie Carlucci; Margaret Esapa; Scott Ellis; Peter Widdowson