Mapping the antigenic landscape of Multiple Myeloma to inform the development of precision cancer immunotherapies

Applications must be complete, including both references, by 14^th January 2022 at 5pm

Applications must submit an online application: https://www.uclbbk-mrcdtp.ac.uk/apply

This is an exciting opportunity for a talented and committed scientist to undertake doctoral research at the cutting edge of immuno-genomics. You will undertake deep genomic analysis of sequencing data on tumour cells to derive shared and unique neoantigens, and validate these for cell therapy using in vitro assays. You will work with a team at the forefront of their respective fields: Achilles Therapeutics who are a leader in neoantigen-based cell immunotherapies (Supervisor: Prof Sergio Quezada) and academic partners at UCL Cancer Institute (Prof Kwee Yong and Dr Lydia Lee, Myeloma Biology and immune microenvironment) and University of Oxford (Dr Sarah Gooding, Myeloma Genetics).

Scientific Background:

Despite considerable therapeutic advances in the last two decades, multiple myeloma(MM) remains both common and incurable and within the top 10 causes of cancer deaths. There is therefore an unmet need for new therapeutic strategies for this cancer. One of the challenges is the paucity of selectively expressed tumour antigens in this cancer.

MM is a genetically diverse cancer however there are key recurrent translocations. We hypothesize that these recurrent fusion events will result in shared neoantigens in subpopulations of patients. However the particular tumour neoantigens and the subpopulations of patients in which they are found need to be defined.

T cells have the ability to detect and kill cells bearing foreign (or neo-) antigens with exquisite sensitivity and there is a growing body of evidence for tumour directed immunity which maintains disease control during disease remission and in pre cancer states (eg smouldering myeloma/SMM). Adoptively transferred T cells are a potent immunotherapy. MM neoantigens are of particular interest as they are likely targets for tumour directed immunity and will potentially serve as tumour-specific targets for immunotherapeutic strategies.

Project Aims:

·      Identify distribution of shared fusion events amongst patients to create a comprehensive map of potential personal/shared tumour neoantigens;

·      Validate presence of neoantigen-reactive T cells in patients with MM and SMM, characterise them phenotypically and validate their cytotoxic capability;

·      Provide proof of concept of expansion and activity of neoantigen-reactive T cells for potential clinical development.

Scientific Significance: This project is the first comprehensive study of MM neoantigens, potentially leading to the discovery of new targets for MM treatment. Following this project, these neoantigens could be used for the development of off the shelf T cell therapy-based treatments and/or prophylactic vaccines for patients with SMM.

Skills learned: Extensive bioinformatics experience (Bulk RNA, WG, WE, TCR, scSEq analysis) including innovative new pipelines, primary tumour and T cell isolation and in vitro culture, complex coculture systems, TCR sequencing, deep T cell phenotyping by flow and mass cytometry and dimensionality reduction analysis