Kennedy Trust Prize Studentships
Combining in vivo, in vitro and in silico neo- and recall-antigen human challenge models to evaluate immunomodulatory therapeutics
- Project No: KTPS-Clinical-7
- Intake: 2021 KTPS-Clinical
Therapeutic modulation of the human immune system is now established in clinical practice, most notably in the treatment of autoimmune disease and cancer. As knowledge of the diversity and function of the cellular and molecular landscape has expanded, so have the potential number of druggable targets and agents that may modify them. Early determination of the safety, pharmacology and proof-of-concept of immunomodulatory investigational medicinal products (IMP) is vital to ensure rapid, efficient translation of scientific insight into patient benefit.
The T-cell dependent antibody response (TDAR) to a neoantigen, coupled with quantification of a delayed-type hypersensitivity (DTH) reaction to re-exposure (recall) is an established paradigm for evaluating pre-clinical immunotoxicity. Requiring the successful interaction of multiple cell types and signalling pathways to facilitate a cellular and humoral immune response, this assay has recently been repurposed to evaluate the efficacy of therapeutics designed to modulate the human immune system through diverse mechanisms.
In vivo human experimental challenge paradigms afford unique pre-clinical insights into the pharmacokinetic, and crucially, pharmacodynamic properties of drugs in their target species. Whilst the TDAR/DTH paradigm has been employed in early phase trials, an absence of standardisation regarding study design, choice of antigen, dose (neo and recall), timing of interventions, metrics of immune modulation and statistical analysis impair interpretation and prevent benchmarking of either drug classes (and thus their target) or individual agents. The absence of companion in vitro assays based on the same antigen, or in silico mechanistic models capable of generating meaningful predictions from acquired data, further impairs utility.
This project seeks to establish a gold-standard in vivo human TDAR/DTH challenge model based around the antigen keyhole limpet haemocyanin (KLH). The pharmacology of, and immunological interaction between, both neo and recall antigen doses will be explored to determine optimal sensitivity for therapeutic modulation and to inform future trial design based on both frequentist and Bayesian approaches. The systemic (antibody titres, ELISPOT, FACS) and local (erythema, oedema, suction blister over DTH) in vivo response to antigen exposure will be investigated to characterise and interrogate the cellular and humoral response at the tissue level. In parallel, an industry-derived in vitro assay of both human T and B-cell function will be adapted to permit the pharmacodynamic interrogation of established immunomodulatory drugs in this system. Quantitative in silico mechanistic models of the immune response will be established and iteratively refined based on experimental data to determine their ability to replace or reduce pre-clinical animal studies and predict human PK-PD relationships. It is anticipated that this body of work will have immediate impact, enabling earlier pre-clinical go/no-go decisions regarding candidate IMPs and informing indication-selection based upon derived biological insights.
The successful applicant will benefit from a supervisory team comprised of experts in immunology, mechanistic modelling, clinical pharmacology, early phase drug discovery and Bayesian statistical approaches. They will be encouraged to integrate these disciplines to generate novel, impactful paradigms that promote translational science and accelerate the discovery of therapeutics. Independent thought and the challenging of established dogma will be actively encouraged.
A broad but comprehensive training will be provided in experimental medicine approaches and immunological techniques (cell isolation, FACS, ELISA, primary cell culture, functional assays). This will be supported by exposure to a core curriculum of lectures (inflammation, genomics, epigenetics, translational immunology, data analysis), regular departmental seminars and access to diverse learning opportunities across the University. Appropriate hands-on support will enable the rapid accruing of necessary skills and the ability to undertake work independently. Specific emphasis will be placed on the development of specialist knowledge in the fields of in silico immune modelling, systems pharmacology and Bayesian trial design. As such, candidates with a background in mathematics or applied statistics will be favoured.
If appointed, the applicant will work in both the world-renowned Kennedy Institute and Botnar Research Centre, with access to appropriate clinical research facilities (Clinical Trials Unit, Nuffield Orthopaedic Centre). State-of-the-art equipment with unparalleled levels of accompanying technical expertise will enable the conduct of field-leading research. The supervisory team brings a unique combination of experience in basic and clinical science undertaken from both an academic and industry perspective and interaction with the latter will be encouraged.
Students will be expected to present data regularly to the department, attend and disseminate data at national and international conferences as well as publish in high-impact journals.
- Brown LV, Gaffney EA, Wagg J, Coles MC. Applications of mechanistic modelling to clinical and experimental immunology: an emerging technology to accelerate immunotherapeutic discovery and development. Clin Exp Immunol 2018; 193(3): 284-92.
- Collinge M, Cole SH, Schneider PA, Donovan CB, Kamperschroer C, Kawabata TT. Human lymphocyte activation assay: an in vitro method for predictive immunotoxicity testing. J Immunotoxicol 2010; 7(4): 357-66.
- Lebrec H, Molinier B, Boverhof D, et al. The T-cell-dependent antibody response assay in nonclinical studies of pharmaceuticals and chemicals: study design, data analysis, interpretation. Regul Toxicol Pharmacol 2014; 69(1): 7-21.
- Saghari M, Gal P, Ziagkos D, et al. A randomized controlled trial with a delayed-type hypersensitivity model using keyhole limpet haemocyanin to evaluate adaptive immune responses in man. Br J Clin Pharmacol 2020.
- Swaminathan A, Lucas RM, Dear K, McMichael AJ. Keyhole limpet haemocyanin - a model antigen for human immunotoxicological studies. Br J Clin Pharmacol 2014; 78(5): 1135-42.
- Experimental medicine
- Molecular, Cell and Systems Biology
- Challenge studies
- Drug discovery
- T cells
CONTACT INFORMATION OF ALL SUPERVISORS
Prof. Mark Coles, Kennedy Institute Of Rheumatology
Dr. James Fullerton, Botnar Research Centre
Prof. Duncan Richards, Botnar Research Centre
Dr. Jane Holmes, Centre for Statistics in Medicine