Clinical advances in tumour immunotherapy based on immune checkpoint blockade have proven that the ability of the immune system to eradicate tumours can be harnessed in the clinical setting and have reignited an interest in immunotherapies. While immune checkpoint blockade with drugs such as ipilimumab is effective in unleashing the cytotoxic effector functions of tumour-infiltrating CTL, many patients have to stop this form of treatment due to adverse events. One of the most frequent adverse responses observed upon ipilimumab treatment is caused by inflammation of tissues such as the gut and represent a direct consequence of systemic tissue-unspecific immune checkpoint blockade. Thus alternative strategies are needed such as tissue-specific targeted approaches promoting cytotoxic effector functions in the tumour and leave healthy tissues unaffected. These approaches can potentially minimise adverse responses making them suitable for a wider range of patients. This study aims to explore the targeted deposition of nucleic acid (NA) adjuvants in tumour tissue as a novel strategy to promote the effector function of tumour infiltrating cytotoxic effector cells. NA adjuvants are particularly suited for induction of anti-tumour immunity since they induce strong T helper type I responses and cytotoxic effector functions. Furthermore, it has been demonstrated that untargeted deposition of NA adjuvant in the tumour tissue promotes anti-tumour immunity. This has been shown in both mouse models and in the clinical setting as exemplified by the treatment of basal cell carcinoma with the Toll-like receptor (TLR)7/8 agonist imiquimod. However, unlike topical application, systemic application of TLR agonists is difficult to manage in a clinical setting due to unspecific widespread innate immune activation, which limits the application of TLR agonists in tumour immunotherapy. The targeted deposition of NA TLR agonists in the tumour tissue represents a strategy that has the potential to allow for efficient local promotion of anti-tumour immunity while at the time avoiding adverse responses on a systemic level.
The project will build on our expertise on NA adjuvants and the generation of biochemical conjugates of NA adjuvants and antibodies. A completed proof of principle study established the benefit of site-specific antibody-NA adjuvant conjugates (unpublished data). However, their efficacy in delivering adjuvant to the tumour, their effects on the tumour microenvironment and their ability to raise anti-tumour immune responses remain important questions which we aim to address in this follow-up study.
Objectives: In this study we will also investigating the functional consequences of altering the antibody isotype and delivering NA adjuvants stimulating different TLR via different routes of administration. The objective is to understand how the biochemical design and administration route of antibody-adjuvants shape the anti-tumour immune response (potency) and reduce systemic immune activation (safety).
The overall aim of the project is to characterise and compare the immunotherapeutic response of various antibody-adjuvant conjugates differing in the antibody isotype, the adjuvant and the route of administration. A better understanding of the mechanisms underlying the anti-tumour immune response induced by specific antibody-adjuvant conjugates will allow to define the structure-function relationship enabling the design of optimised antibody-adjuvants targeting tumour markers.
The project entails:
1. The cloning, expression and purification of modified antibodies.
2. The generation and purification of antibody-adjuvant conjugates.
3. The characterisation of antibody-adjuvant conjugates in various in vitro assays including cell-based immunoassays.
4. The optimisation of a humanised mouse tumour model for studying the efficacy of antibody-adjuvant conjugates in inducing anti-tumour immunity.
5. The comparison of different antibody-adjuvant conjugates in the humanised mouse tumour model.
Key Responsibilities:
• To undertake the research project in line with the project aims
• To communicate effectively, orally and through written media, undertake presentations at scientific meetings, maintain excellent records, prepare reports and manuscripts for publication in peer-reviewed journals.
• To interact regularly and effectively with the supervisors and interact appropriately and effectively with other staff
• To fulfil the requirements of the University PhD programme and to undertake specific training as required by the host institutions
In addition to meeting all the academic, security and residency requirements, you will have: • an academic background in cellular or molecular biology or immunology. • knowledge of most relevant imunoassays • a demonstrated aptitude in a laboratory setting and motivation to undertake research • a demonstrated interest in the field of study and ability to work accurately and precisely • demonstrated excellent oral and written communication, and IT skills • a previous experience in one or more of the key interest areas as an advantage
About MHRA
The Medicines and Healthcare products Regulatory Agency enhances and improves the health of millions of people through effective regulation of medicines and medical devices, underpinned by science and research.
About the Group
The Immunotherapy group, within the Division of Biotherapeutics and Advanced Therapies, is a leader in the development of biological reference materials and evaluation of the safety and potency of biotherapeutics. The group also pursues an ambitious research programme into immunotherapeutic cancer medicines.
Awarding institution
The Comprehensive Cancer Centre at King’s College London is the academic arm of one of the leading cancer centres in Europe and brings together world-class clinical services, research and education for the benefit of cancer patients in south east London and beyond. The School of Cancer and Pharmaceutical Sciences is situated with the Faculty of Life Sciences & Medicine and is committed to improving patient response through fundamental science discovery.
The project supervisors areDrs Sandra Diebold (MHRA) and James Arnold (KCL). The student will be based primarily at MHRA South Mimms campus with yearly secondments to KCL.
Qualification requirements for King’s College London
As a candidate, you will be a motivated individual with a keen interest in undertaking research in the field of vaccines. You will have or expect to achieve a 1st or 2:1 (or international equivalents) in a relevant subject.
To apply
Send (i) your CV including the name and contact details of two academic referees and (ii) a personal statement of no more than 1000 words explaining your interest in this project and aspirations for undertaking a PhD to [Email Address Removed] by 31 January 2023.
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