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Cancer Research UK City of London Centre Development Fund Awards
The annual CRUK City of London Centre Development Fund provides short-term, pump-priming funding to support innovative research projects and inspirational, proof-of-concept cancer research. The scheme offers one year funding for up to £20,000 per award. Multidisciplinary applications are particularly encouraged.
The following projects have been selected for 2022 funding:
Immunogenicity of proteasome-generated spliced peptides derived from fusion-genes in childhood acute and chronic myeloid leukaemia
Led by Dr Michele Mishto
KCL
Co-applicants: Richard Dillon (KCL), Hugues De Lavallade (KCL), Rob Sellar (UCL), James Reading (UCL), Jeff Davies (QMUL)
- Project details
Acute myeloid leukaemia (AML) in children remains a significant unmet, with high prevalence of specific gene fusions. We hypothesize that these fusion-proteins could be well presented by proteasome-generated spliced peptides, and recognised by CD8+ T cells. Their cytotoxicity could be used to attach AML by developing novel immunotherapies. The project will verify this hypothesis by applying a multidisciplinary strategy, which ranges from bioinformatics to clinics though biochemistry, molecular and cellular immunology.
The project is funded on the unique expertise of the applicants, who are located at King’s College London, University College London and Queen Mary University of London, and with the support of the Francis Crick Institute
One bottleneck in developing this combination therapy further is that many factors, which are central to its successful delivery, remain poorly understood. This is because the laboratory models that researchers have been using, do not adequately mimic the complexity of the human body. Consequently, it is now necessary to improve these models and use new techniques to obtain more and better research data from them. Here, we will pilot new analysis workflows, which will allow us to apply for more funding to develop this therapy combination.
Investigation Of the Tumour Microenvironment during acute lymphoblastic leukaemia (ALL) Therapy with Blinatumomab
Led by Dr Sara Ghorashian
UCL Cancer Institute
Co-applicant: Dr Shahram Khordasti (KCL)
Generation of a novel in vivo tool to investigate translational alterations during tumorigenesis and in response to chemotherapy
Led by Dr Diu T.T. Nguyen
Barts Cancer Institute
Co-applicants: Dr Maria Secrier (UCL)
Analysing stimulation of CAR-T by stressed tumour cells to understand the mechanics of a more functional CAR
Led by Dr Bela Wrench
Barts Cancer Institute
Co-applicants: Dr Alice Giustacchini (UCL), Prof John Maher (KCL)
- Project details
We have developed a novel therapeutic concept in which CAR-T cells are rendered more proliferative and endowed with greater cytolytic activity when exposed to B-ALL blasts that have been pre-treated with a metabolic stressing agent that starves cells of arginine. With the support of the CRUK City of London Centre Award we will now analyse the molecular determinants of this phenomena using single cell proteomics via CyTOF, then expand to an in vivo testing platform to identify its potential pre-clinical benefit. Finally, we will test the portability of this effect to other tumour types to assess whether metabolic stress can be used more widely to enhance the anti-cancer effect of CAR-T.
Old drugs new tricks: Breaking myeloid-CAR T-cell immune suppression in neuroblastoma
Led by Dr James Arnold
King's College London
Co-applicants: Prof John Anderson (UCL)
- Project details
Chimeric antigen receptor (CAR) T-cell immunotherapy represents a potentially powerful approach for treating neuroblastoma, however, immune suppressive macrophages in the microenvironment represent a potential barrier to robust clinical outcomes. This project will employ a screen of FDA-approved drugs to block the immune suppressive activity of macrophages on CAR T-cells. These drug candidates will be investigated using in vitro an in vivo models of neuroblastoma. As the drugs within the screen are FDA-approved, it will permit their rapid translation to the clinic for improving the efficacy of CAR T-cell immunotherapy in neuroblastoma.
CRUK UCL Centre Development Funds success story:
One of the first CRUK UCL Centre Development Funds, awarded in 2011 has contributed to a recent Cancer Cell publication on the molecular signatures of regression of the canine transmissible venereal tumor (CTVT) by Professors Ariberto Fassati (Division of Infection & Immunity) and Stephan Beck (UCL Cancer Institute). This study used global transcriptional, methylation, and functional pathway analyses on serial biopsies of vincristine-treated CTVTs. By comparing CTVTs that regressed to CTVTs that did not regress after vincristine treatment, they found that regression occurs in sequential steps, starting with an acute inflammation. The chemokine CCL5, which attracts immune cells into the tumour site, was identified as a possible driver of CTVT regression and changes in gene expression were associated with methylation changes at specific intragenic sites. These results underscore the critical role of host innate immunity in triggering cancer regression.
