Cancer gets the message.

John writes ...

Some personal history.
One sunny morning in May 2011 I went to the local teaching hospital to receive a diagnosis based on a biopsy that had been taken a few days earlier. The result was very clear: the pigmented patch on the shin of my left leg was, as suspected by me and by the dermatology consultant, a melanoma, which is the most aggressive type of skin cancer (1). It was a very early-stage melanoma and was unlikely to have spread. The nurse-practitioner who conveyed the news indicated that the melanoma would be removed by surgery followed by a skin-graft. I had that treatment a few weeks later and having chosen to receive only local anaesthetic, was able to watch with interest the whole procedure. I would also have regular checks for a year to see whether or not the cancer had spread – which fortunately it never did.

Main entrance of the Royal Devon and Exeter Hospital. Credit: Royal Devon University Healthcare NHS Foundation Trust.

During the conversation about the diagnosis and projected treatment, the nurse-practitioner also explained that, at the time, there were no effective chemotherapies for melanoma (although some had been tried) and so, if the cancer had spread, surgery would again be the treatment. However, during the 15-minute drive home, I listened to a radio programme that presented recent advances in medical science. The first item that came up was the approval by the NHS of an immuno-therapy for treating advanced melanoma. In other words, the treatment involved stimulation of the body’s immune system to specifically target the melanoma cells. There followed testimonies from patients whose advanced melanomas had been treated very successfully by the new therapy. Indeed, one woman said that secondary tumours in her liver had been destroyed so quickly that for a while, the liver had holes and gaps in it, as the body’s regeneration mechanisms could not keep up with the rate of destruction of cancer cells. As I listened to this during my brief car journey my mood was significantly elevated. I realised that, if by chance the medics are wrong and my melanoma does spread, there is now a treatment for it. The immuno-therapy was widely taken up by doctors treating metastatic melanoma (i.e. melanoma which had spread to other parts of the body) and among its recipients was former USA president, Jimmy Carter who was treated very successfully at the age of 90!

Former USA President Jimmy Carter at the age of 90. Credit: LBJ Library.

The treatment spreads.
The announcement of an effective immuno-therapy for melanoma immediately led to the idea that similar therapies could be introduced for other cancers. It would require the identification for each cancer of a specific antigen for that cancer, for example, a protein on the surface of the cancer cells. The patient’s immune system would then be stimulated to raise antibodies to target the cancer cells, as had been done for melanoma. Immuno-therapeutic treatments have now been developed for a wide range of different cancers or cancer sub-types whilst at the same time, several different versions of the original treatment have been developed, depending on which protein(s) is/are targeted (2). More recently, immuno-therapy has been combined with genome editing and genetic modification in two slightly different ways in order to cure very difficult cases of childhood leukaemia (3).

Alyssa, cured of her aggressive leukaemia by an immuno-therapy that also involved genome editing and genetic modification techniques. Credit: Great Ormond Street Hospital.

Back to the 1960s.
In targeting antigens, whether in a cancer cell or a pathogen, we are targeting proteins, albeit that some of them may be modified, for example by the addition of carbohydrate groups to make glycoproteins. It is therefore helpful to remind ourselves of a couple of features of the synthesis of proteins. The structure of proteins is encoded in DNA with, for the most part, one protein being encoded in one gene. But the genes are separated from the sites in the cell where the proteins are made, so how does the code in a gene direct the synthesis of a protein. Several scientists, including Sydney Brenner at Cambridge, predicted that genes were copied into ‘messenger’ molecules that took the code to the sites of protein synthesis. Two international teams (French/British/American) assembled especially for the job, and working in two different labs in the USA, confirmed that this hypothesis was correct. The messenger molecules are made of RNA and are hence known as messenger RNA. In bacteria, the messenger RNA (mRNA) molecules are relatively short-lived, as described in the papers published by the two teams (4) but in other organisms, the longevity of mRNA molecules varies between genes.

Sydney Brenner, FRS, Nobel Laureate (1927 – 2019) in 2002, the year in which he was awarded the Nobel Prize. Credit: www.youtube.com.

Working with messages.
It goes without saying that we have come a very long way since those early discoveries. We now have means of identifying the mRNA copied from a specific gene amongst the thousands of mRNAs copied from other genes. This enables us to ascertain when a gene is actively being copied so that we can look at the patterns/timings of expression of particular genes in relation, for example, to particular life events. Thus, in my field, it has been possible to study the expression of different genes by measuring the amount of their particular mRNAs in relation to the phases of the cell division cycle (5).
Further, it is now possible to make mRNA molecules corresponding to specific genes. This is not without its difficulties – single-stranded RNA molecules such mRNA are susceptible to breakdown when existing outside the cellular environment. This is true both of those messages which are longer-lived in the cell and those which are shorter-lived. However, methods of improving very significantly mRNA stability have been developed – an advance which has opened up a huge range of possibilities.
 
Bringing everything together.
Earlier in this article, we saw that many cancers can now be treated by immuno-therapy, inducing the body to make antibodies to particular cancer proteins (antigens), often by injecting the patient with the purified protein. But what if we asked a patient’s body to actually make an ongoing supply of the antigen to achieve a higher level of antibody production? How would we do this? I am sure that many of our readers have already reached the correct answer to that question but in order to complete my story, I am going to return to the COVID pandemic. The key feature which I want to emphasis is that several of the most successful vaccines did not involve injection of an antigen (the spike protein) but the mRNA encoding the antigen – so our own cells made the spike protein and our immune system made antibodies against it. Brilliant!
 
The success of the Covid vaccines almost immediately led to questions in the cancer research community – if it works for vaccination surely mRNA technology could also work for immuno-treatment of cancer. And the question has now been answered, as revealed in an announcement in February this year that clinical trials involving mRNA-driven cancer immune-therapy had been initiated at Hammersmith Hospital, London (6). This announcement was followed just last month by the news that a lung cancer patient at University College London Hospitals (UCLH) had been started on immuno-therapy based on mRNA (7). Cancer does indeed ‘get the message’.

Messenger RNA-based immuno-therapy may be delivered by simple injections. Credit: BBC News.

Incidentally, both the announcement from UCLH and the BBC’s coverage of this development talked of a ‘novel cancer vaccine’, based on the similarity of the technique to that used in Covid vaccines. However, as I have emphasised elsewhere (8), this is not actually a vaccine (it is not used to try to prevent cancer) but a treatment for use when someone actually has cancer.
 
Concluding comments
I have told a story here that entwines the applications of research from three different areas of biological/biomedical science, namely cancer cell biology (including cell division), immunology and molecular biology. As a long-term member of the molecular biology community (including work with mRNA) I am delighted that the discoveries made by scientists are being applied for human benefit. As a Christian I believe that science is a gift from God – curiosity about how the world works is embedded in the human species and some of us are privileged to exercise that curiosity in our work. Equally, I believe that it is important to use our knowledge wisely and where possible in fulfilling the commandment ‘Love your neighbour’ in practical ways, exemplified by the work described here.
 
John Bryant

Topsham, Devon
September 2024
 
(1)   The consultant also told me that long-distance runners were probably at greater risk of getting skin cancer on the legs than the general population.
 
(2)   Immunotherapy for Cancer – NCI.
 
(3)  ‘Introduction to Bioethics’(2nd Edition), Bryant and la Velle, Wiley/Blackwell (2019), p. 139; Cancer therapy involving genome editing cures another child’s leukaemia – Genomics Education Programme (hee.nhs.uk),    Meet Alyssa | Great Ormond Street Hospital Charity (gosh.org).
 
(4)   Discovery of messenger RNA in 1961 (Pasteur.fr).
 
(5)   For example, Genes encoding two essential DNA replication activation proteins, Cdc6 and Mcm3, exhibit very different patterns of expression in the tobacco BY-2 cell cycle – PubMed (nih.gov).
 
(6)   First UK patients receive experimental mRNA therapy for cancer | NIHR.
 
(7)  First UK patient receives innovative lung cancer vaccine: University College London Hospitals NHS Foundation Trust (uclh.nhs.uk).
 
(8)   Link to author's interview on Youtube: www.youtube.com.