The following is a two-part collaborative piece by Dr Alexander Gray, Chief Medical Officer for IDEA Pharma and UCL alumnus, and Gordon Weng-Kit Cheung, a researcher at the UCL Cancer Institute. The article highlights the promise and potential of immunotherapy in the fight against cancer, featuring the early pre-clinical development happening right here at UCL.
In the article that follows, Gordon WengKit Cheung outlines the evolution of one of the most exciting developments in cancer treatment: immunotherapy, specifically CAR T-cell therapy. Back in 1989, as a fresh-faced medical student starting at UCL, the idea that you could transplant targeted immune cells into patients seemed both exciting and unlikely. In the following two years, I became increasingly fascinated in the study of the immune system with all its marvellous intricacy, and the way in which it utilised multiple, parallel approaches to limit the harm that pathogens can do to the human body. This led me to an intercalated BSc in Immunology, at which point I became interested in primary immunodeficiencies such as severe combined immunodeficiency (SCID).
Little did I realise at the time that unravelling the underlying causes of these rare but devastating conditions would have a significant impact on our understanding of the function — as well as the dysfunction — of the immune response, and for the development of anti-cancer therapies. An example of this is X-linked agammaglobulinaemia (also known as Bruton-type agammaglobulinaemia after the paediatrician who originally described it), a disease that stems from the failure to generate mature B lymphocytes and manifests as recurrent infections in childhood. It was not established until 1993 that mutations in a tyrosine kinase encoded on the X chromosome were responsible for the disorder. Bruton’s tyrosine kinase (BTK), as it was named, is of critical importance in B cells: it is required not only for B-cell receptor signalling, but also for co-stimulatory signals that are essential for their maturation and differentiation. While this detailed understanding did not lead directly to a treatment for Bruton-type agammaglobulinemia, it did aid the recent development of BTK-inhibiting drugs that have proven to be of high clinical value in the treatment of B-lineage leukaemias and lymphomas. This story is a great example of how unravelling the complexity of one disorder can ultimately lead to the development of a different but highly useful anti-cancer therapy.
Back in the 1990s, little work was being done on cancer immunotherapy. Common misconceptions were that the immune system was uninterested in cancer cells, because they were “self”, or that the immune system failed to target cancer cells because it had become “tolerant” to the antigens that they express. Intensive research in the last few decades has largely put paid to the idea that the immune system doesn’t recognise tumour cells as “foreign”. It is now evident that the immune system is indeed able to recognise tumour cell antigens, many of which are derived from the aberrant expression of mutations that arise within the tumour cells. Recent research on the range of tumour antigens expressed during cancer development found that tumours with high neoantigen expression, but with a lower number of different antigen types, are associated with significantly longer times to cancer progression than those with low, but more heterogeneous, expression. In other words, if a patient’s cancer expresses a small range of antigens in large amounts, the immune system seems to do a better job of keeping it under control.
Why then, if tumour cell antigens are recognised by the immune system, are they not killed before they develop into clinically meaningful disease? Tumour cells are adept at evading the immune system by mechanisms including impaired tumour antigen processing and presentation by tumour cells, dysfunction of antigen-presenting cells, and defective co-stimulation and/or co-inhibitory pathways related to immune checkpoint blockade. Tumour cells are therefore able to “put the brakes” on the immune response. Different tumour types have different patterns of this effect: in some, few immune cells ever make contact with the tumour (an “immune desert”); others have a halo of immune cells that do not penetrate the tumour (“immune excluded”); and others have significant immune cell infiltration, but the cells are largely non-functional (“inflamed tumours”).
This brings us to the work being done by Gordon under Martin Pule’s team at UCL, which aims to re-galvanise the immune response against tumours. While these promising chimeric antigen receptor (CAR) T-cell therapies (discussed in detail below) represent a major hope in the fight against both solid and “liquid” tumours, it is evident that we need other immunologic tools if we are to be successful in limiting cancer growth and metastasis. To that end, there has been an explosion in our understanding of the pathways of stimulation and suppression of the immune response to cancer. When interacting with tumour cells, tumour-infiltrating lymphocytes have their immune responses downregulated through the programmed cell death protein (PD)-1/PD-L1 pathway. Non-small cell lung cancers (NSCLC) expressing significant amounts of PD-L1 have been found to be amenable to treatment with monoclonal antibodies targeted against either PD-L1 or its binding partner PD-1. These antibodies — now available to prescribe to patients with NSCLC — have demonstrated significant benefits in prolonging survival with a relatively low toxicity burden. More classes of these so-called “checkpoint inhibitors” are being investigated, as there are several different protein interactions that inhibit immune cells from being activated to target cancer cells. Many of these are in the early stages of clinical development, where some are used alone but others in combination with other checkpoint inhibitors or anti-cancer strategies. As some tumours are “immune deserts” or “immune excluded”, the immune system needs to be boosted in its response to tumour antigens. This can be achieved using tumour vaccines, several of which are currently in development. They are also being looked at in combination with checkpoint inhibitors; effectively removing the brake whilst flooring the accelerator on the immune response.
In the 20 years that I have worked in the pharmaceutical industry, I have never felt so optimistic that we can make a big difference to the outlook for cancer patients. The current revolution in immunotherapy goes well beyond targeted drug therapy: by utilising the power of the immune system, we have the opportunity to develop multiple approaches to cancer therapy that could not only dramatically extend the lives of some cancer patients, but also deliver this promise to a much broader range of patients and tumour types, and for longer periods of time. Back in 1989, I had no inkling that my early forays into understanding the immune system would lead me down the path of cancer treatment. As you sit in one of the many teaching sessions throughout medical school, just remind yourself that what you learn today may end up being far more valuable than you ever envisaged.
By Alexander Gray
Chief Medical Officer, IDEA Pharma