Promoting cancer cells' antigen presentation for serving as better targets for T cell immunotherapy
Primary Supervisor: Dr Shisong Jiang
Cytotoxic T cells (CTLs), which kill tumour cells upon recognition of antigenic peptides presented by the major histocompatibility complex (MHC) on the cell surface, are the goal of precision medicine including immunotherapies. However, tumour cells engage several mechanisms to avoid the presentation of tumour-specific antigens (TSAs or TAAs) and consequently, they can escape CTL-mediated cell death. This contributes to the failure of many immunotherapies to control tumour growth even when immunity (e.g. CTLs) has been properly stimulated. Most immunotherapies targeting antigen presentation focus on professional antigen-presenting cells and rarely on tumour cells themselves, which leads to poor efficacy. Hence, immunotherapies and products that enhance the antigen presentation process in tumour cells are an unmet need. The aim of this project is to develop a small molecule that can facilitate antigen presentation to CTLs. We intend to target two intracellular proteins, namely survivin (SVN) and KRAS, which are TAAs that are important in tumour formation and metastasis. In this project, we will screen small molecules that can specifically target and degrade SVN and KRAS followed by enhanced antigen presentation in the cancer cells. The small molecules can be clinically utilised alone (directly kill tumour cells) or more importantly, in combination with immunotherapies such as tumour therapeutic vaccines. In the case of combination therapy, the dose of the small molecules will be expected less than the single therapy. Ultimately, we hope that this will bring about tumour cell death via the action of cytotoxic T cells. We also believe that these molecules can improve the effectiveness of existing immunotherapies. Once the small molecules are characterised and tested in in vitro antigen presentation assays, we will test in the in vivo models the combination therapy of small molecules with tumour therapeutic vaccines. We will collaborate with OVM which is developing therapeutic vaccines (SVN and KRAS). SVN therapeutic vaccine is in Phase I clinical trial. If the small molecules synergise with the therapeutic vaccines, OVM would be interested in licensing-in the technology. The project mentioned here fall into the MRC remit of Discovery Science and Precision Medicine.
Aim 1. Screen and characterisation of small molecules As part of an established collaboration, we have identified and modified small molecules that bind and inhibit SVN. We will further modify these molecules to make them better for antigen presentation inside tumour cells. With that experience, we will identify and screen small molecules targeting KRAS. We will characterise the binding affinity of the new small molecules to the relevant target proteins using techniques including native mass spectrometry and crystal soaking. Optimisation of the key structural parameters of each small molecule will also be performed so as to maximise biological activity.
Aim 2. Test the small molecules on enhancing antigen presentation in tumour cells Here we will engage T cell clones that recognise the antigenic peptides presented by tumour cells. This experimental system is already set up in the Department of Oncology. The small molecules developed can also be tested using in vivo xenograft tumour models. We have previously made and modified small molecules for SVN (LQZ-7I) and, pleasingly, the molecule shows binding and inhibition of tumour cells in our assays.
Aim 3. Combination therapy with tumour therapeutic vaccines OVM is an Oxford University spinout SME that develops tumour therapeutic vaccines. The SNV-based therapeutic vaccine (OVM-200) is in Phase I clinical trial in the UK. The KRAS-based vaccine (OVM-400) is in its development pipeline. The small molecules developed in Aim 1 & 2 will be tested in combination with OVM-200 or OVM-400 in xenograft animal models. If the in vitro work going on well, OVM will license the technology and develop the project further into preclinical and clinical trials.
Oxford Vacmedix UK Ltd (OVM), based in the Oxford Science Park, UK, is a clinical-stage biopharma company that utilizes the novel proprietary platform technology of recombinant overlapping peptides (ROPs). ROPs have been validated as a technology to stimulate broad and strong T cell immunity, therefore, forming a good platform for cancer therapeutic vaccines and diagnostics. The company is a spin-out of the University of Oxford. There are several cancer therapeutic vaccines in the development pipeline. OVM-200 (targeting survivin) is in the Phase I clinical trial stage. The indications are non-small cell lung cancer, ovarian cancer and prostate cancer. OVM-100 (targeting HPV16-E7) is in the process development stage. The indications for OVM-100 are cervical cancer and head/neck cancer. OVM-300 and OVM-400 are in the preclinical stage and target prostate-specific antigen (PSA) in prostate cancer and KRAS in pancreatic cancer, respectively. Moreover, OVM has developed a lateral flow immunoassay (LFIA) for the fast diagnosis of antibiotic resistance to bacterial infections. The student will test the small molecules co-developed by the Departments of Chemistry and Oncology in the vaccine models used by OVM. Moreover, the students will gain hands-on experience in Oxford Vacmedix UK Ltd learning new skills regarding technology transfer and drug development.
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