Combination immunotherapy for solid tumours with oncolytic virus & cognate CAR T-cells

Every year approximately 350,000 new cases of cancer are diagnosed in the UK. Despite modern treatments many patients cannot be cured. Recent scientific discoveries harnessing the immune system to fight cancer are transforming the lives of a small group of patients. Unfortunately, the majority of patients with advanced cancer gain minimal benefit from this approach. This project aims to test an innovative strategy that could enhance the body's ability to fight various cancers. Because the strategy is new, it is vital to test how safe and effective it is in cells grown in a dish and in mice before it is developed for use in human trials. Essentially, it is a project of two halves, using cutting-edge genetic engineering to achieve its goals. The idea is to engineer a virus that will only infect cancer cells. Once inside it is hoped that the virus can render the cancer cells susceptible to attack by killer white blood cells called T-cells. These T-cells, which form an important part of our immune system, would also be genetically engineered to seek out and kill cancer cells. The virus would also be designed to produce a chemical that can enhance the susceptibility of the tumour to immune attack. Further engineering of the T-cells may also be used to improve the way in which they can target tumours. Because of the way in which the experiments are designed, it is hoped that in the future this strategy can be applied to a very large number of patients with many different types of cancer. It is also hoped that the idea underlying the research can be further advanced by making additional changes to both the virus and the T-cell to enhance the treatment's ability to eradicate tumours.

Cancer is a leading cause of death globally. Despite advances in immunotherapy, the vast majority of patients with advanced cancer remain incurable. Adoptive cell therapy using chimeric antigen receptor (CAR)-expressing T-cells has considerable promise, but solid tumours have proved resistant to this approach. There are a number of purported reasons for this including a) a lack of homogenously & selectively expressed tumour-associated cell surface antigens, b) a paucity of "dispensable antigens" expressed by solid tumours (unlike CD19+ malignant B-cells where CAR T-cell therapy has proved particularly effective), (c) poor trafficking of CAR T-cells into the tumour microenvironment (TME) and d) impaired CAR T-cell effector function within the TME.

This proposed research uses in vitro and in vivo experiments (using an immunodeficient mouse xenograft model) to investigate the efficacy and safety of a novel therapeutic strategy combining oncolytic virotherapy in a synergistic fashion with CAR T-cell adoptive cell transfer for the treatment of advanced solid tumours. The proposal is further refined by engineering the oncolytic virus to alter the TME thus rendering it more permissive to immune attack. The CAR T-cells may also be further edited to facilitate their efficacy and longevity. Thus, I aim to demonstrate proof of concept for this novel & synergistic immunotherapeutic combination strategy.

Academic:
Successful implementation of the research strategy will have far-reaching benefits for a number of academic disciplines both within the UK & abroad. The synergistic combination of oncolytic virotherapy & CAR T-cell therapy will be of great interest to basic scientists, translational researchers & Oncologists working in the field of immuno-oncology & cancer immunotherapy. The research is also applicable to other disparate fields such as gene therapy, biomedical & cellular engineering, auto-immunity & infectious diseases. This is elaborated further in "Academic Beneficiaries".

National:
It is generally recognised that CAR-based cellular therapy represents a potential paradigm shift in the management of cancer and that the research community remains on the cusp of exploiting its innumerable applications. Nevertheless, despite compelling work undertaken by Dr Maher and several other key players within the UK, this nation lags behind the USA & China (as well as a number of other countries) in the development of this innovative technology. This proposal aims to contribute in a meaningful way to the field of CAR T-cell therapeutics in the UK so that we can compete more effectively on the world stage. The fellowship will also equip me with the skills necessary to build a future academic career, hopefully allowing me to become a leader in this nascent field, facilitating greater access for UK patients to this potentially transformational technology.

Commercial:
An important aspect of the proposed research, and one that has been appreciated from the time of its initial conception, is the significant potential for commercial exploitation. Having completed an in depth literature search I am of the view that the concept is entirely novel, i.e. there are no articles or patents in the public domain that pertain to the concept. As such, following collection of preliminary data, it is expected that the concept will be patented for future commercial development. Meanwhile, we have taken advice from the Commercialisation Director at KCL and have set-up a 3-way Confidential Disclosure Agreement (CDA) between myself, KCL and BCI. The project is in essence a "proof of concept" and if the strategy can be shown to be both efficacious and safe in an immune incompetent mouse model I would envisage future study in immune competent animals before embarking on rigorous safety analysis and a first in human clinical trial. The process of commercialisation will involve the creation of a formal business entity in partnership with spin out companies allied to KCL & BCI. There may also be potential for engagement with industry partners.

Public:
The proposal has considerable scope for impacting in a positive way on the general public and particularly patients with advanced solid tumours, where there are currently few effective therapeutic options. The large variety of tumours that are potentially targetable with this approach constitutes a very major strength of the proposed concept and ensures that the research can deliver the maximum possible impact for patients with advanced cancer.

Charitable:
The proposed research is perfectly aligned with the aims & objectives of numerous cancer charities & patient advocacy groups. The primary goal of the research is to accelerate progress in the development of effective anti-cancer treatments and ultimately to cure cancer in as many patients as possible. It is my aim to seek collaboration with these organisations to disseminate information about the research and encourage public interest in the emerging field of cancer immunotherapy.

Educational:
The proposal will hopefully serve as a model for cross-disciplinary & cross-institutional collaborative research and I would hope that it may act as a catalyst to foster the educational development of school children, university students and young scientists potentially interested in pursuing a career in biomedical research & clinical academia.