MRC iCASE Partnership - Student Project:

PROMOTING CANCER CELLS' ANTIGEN PRESENTATION FOR SERVING AS BETTER TARGETS FOR T CELL IMMUNOTHERAPY

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.

Working with Oxford Vacmedix UK Ltd (OVM), 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 OVM learning new skills regarding technology transfer and drug development.

Identification and Validation of Cancer Biomarkers and Optimisation of Immunotherapy

Immunotherapy has emerged as a promising strategy for cancer treatment, leveraging the patient's immune system to target tumour cells. This approach offers significant advantages, including enhanced specificity and efficacy, either alone or in combination with traditional treatments such as chemotherapy and radiation therapy. A crucial aspect of immunotherapy involves the development of cancer vaccines, which aim to utilise cancer biomarkers such as tumour-specific antigens (TSAs) or tumour-associated antigens (TAAs) to provoke an immune response against tumour cells bearing these antigens.

While TSAs hold promise as targets for cancer vaccines, they are limited in their applicability across different cancer types and are typically associated with tumours caused by viral infections (e.g., HPV) or mutation-related neoantigens. Conversely, TAAs are more prevalent and represent promising targets for various tumour types. However, cancer cells have evolved mechanisms to evade immune detection, such as downregulating MHC molecules and surface antigen presentation to avoid immune surveillance. Additionally, TAAs may be recognised as self-antigens by the host immune system, leading to immune tolerance and a reduced immune response. Consequently, utilising TAAs as vaccines may not elicit a robust immune response, and even if immunity is generated, the effectiveness of killing tumour cells may be compromised due to the invisibility of cancer antigens on the cell surface.

To address these challenges, we focus on a proof-of-concept project employing a tumour-associated antigen (TAA) known as baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5), also named survivin (SVN), as our model. Overexpressed in most tumour types, SVN plays a critical role in regulating cell mitosis as a component of the chromosomal passenger complex and inhibiting extrinsic and intrinsic apoptosis. Our approach aims to amplify cancer cell visibility for the host immune system using SVN-specific small molecules or PROTACs.

Simultaneously, while enhancing cancer cell visibility, we aim to bolster host immunity through the development of an innovative neoantigen-like SVN-based cancer vaccine. We've pioneered a recombinant overlapping peptides (ROP) vaccine design platform, adept at converting TAAs into neoantigen-like vaccines. This technology led to the establishment of a university spinout company and accelerated the translation of the technology into medical products. Over the last decade, we've advanced an SVN-based ROP vaccine from conceptualisation to preclinical trial, GMP manufacture, and clinical trial. A T cell-based diagnostic received regulatory approval for clinical use in 2024.

Additionally, the lab has pioneered the development of a tumour-specific antigen (TSA)-based vaccine. By targeting HPV-E7, we've formulated an ROP-based vaccine designed to treat HPV-infected individuals and halt the progression to HPV-related malignancies. Encouraging preclinical data supports our efforts, and our next objective is to advance this vaccine candidate into clinical trials. 

As we progress our research on recognised biomarkers like SVN and HPV-E7, we also plan to explore additional cancer biomarkers for future development. By combining bioinformatic tools with our wet-lab technologies, we are dedicated to identifying diagnostic and therapeutic biomarkers in challenging cancers such as pancreatic cancer and glioblastoma.

Moreover, the lab is currently investigating mechanisms of MHC downregulation in the tumour microenvironment (TME), aiming to convert this negative regulation to enhance immune recognition of tumour antigens.

Our objective is to leverage our expertise in translational research to discover and validate cancer biomarkers and to develop them into diagnostic and immune therapeutic modalities, ultimately benefiting cancer patients.

Demin Li, Honorary Researcher

Wenshu Lu, Visiting Research Fellow

Yuqian Ou, DPhil Student

Sichen Liu, DPhil Student

Constantinos Demetriou, DPhil Student

Hanjun Zhao, DPhil Student

Zachary Rawlinson, DPhil Student

Wynne Wijaya, MRes Student

Alexander Stephens, Biotech Industry, UK

Yihan Zhou, Research Assistant, Harvard Medical School, USA

Cedric Song Chan, PhD Student, University College London, UK

Jian Wang - Associate Professor, Southwest University, Chongqing, China

Rong Hu, Attending Doctor,  Assistant Professor, Department of Otolaryngology Beijing

Tongren Hospital, Capital Medical University, China

Sophie Owen - PhD Tropical Medicine, Liverpool School of Tropical Medicine, UK

Neha Vashist-Postdoctoral Researcher, Würzburg, Bavaria, Germany

Jason Huang - Associate Medical Director, Oncology, Asia-Pacific at Merck Group, Singapore

Qiongyu Chen - Jackson Laboratory, Bar Harbor, ME, USA

Hongwei Zhang - Associate Chief Physician, Beijing You'an Hospital, Capital Medical University, China

Hai Hong - Associate Professor, Sun Yat-Sen University, China

The phase I clinical trial of cancer therapeutic vaccine OVM-200  at The Christie Hospital in Manchester was featured on ITV's Granada News on Wednesday 7th September 2022.

Read the full article and watch the video report here: Chorley mum with ovarian cancer first in North West to get new vaccine trialled at the Christie