Ask a group of oncologists what the next big thing in cancer therapeutics is, most will tell you personalised mRNA vaccines. Why such consistency? Well, the answer lies in the confluence of several disparate technologies and the relatively disappointing progress of getting durable responses with many of the new and costly tyrosine kinase inhibitors, with a few notable exceptions.
The belief that there really is something happening in this field has led the UK Government to announce a new partnership to boost research into vaccines for cancer this past January. A memorandum of understanding was signed by the Health Secretary, Steve Barclay, to explore personalised mRNA vaccines with the German company BioNTech who co-developed the leading COVID-19 vaccine with Pfizer. This unique collaboration promises to deliver 10,000 personalised therapies to NHS cancer patients by 2030 through the creation of a 'cancer vaccine launch pad'. A new centre will open in Cambridge to co-ordinate both the science and clinical strategy.
Is this all hype, complete with space age nomenclature, just generated by highly paid PR consultants to both industry and government or is it really the most promising breakthrough in cancer treatment so far this century?
Using mRNA to encode useful proteins in vivo has been around in the lab for years. But the COVID-19 vaccine programme driven by BioNTech and Moderna has shown how quick to produce and how potent mRNA-based products can be. Specific epitopes can be sequenced, and unlimited quantities of functional antigen produced from micrograms of RNA within weeks. And the patient becomes their own factory. The quality control, storage, side effect profile, packaging, and delivery strategy have all been worked out.
The second key factor driving this newfound optimism in immuno-oncology is the partial success of the checkpoint inhibitors pembrolizumab, nivolumab, atezolizumab, and ipilimumab in a wide range of cancers. For many years melanoma and renal cell cancer have been found at least partially responsive to a variety of immune approaches from interferon, interleukin-2 to whole cell vaccines.
The change came in 2015 when the FDA-approved nivolumab for metastatic non-small lung cancer in patients who had failed on platinum-based doublet chemotherapy. Although remarkable and long-lasting responses can occur, most patients relapse within 2 years. And predicting responses by measuring tumour mutations or identifying tumours with high PD1 or PDL1 levels is relatively haphazard. But proof of principle that immune strategies can work has now been seen across a whole range of cancers, including breast, colon, bladder, cervix, pancreatic, head and neck, as well as lung.
The third driver in this jigsaw puzzle is the speed at which DNA sequence data can be obtained from clinical samples. What used to take weeks can be achieved in seconds and large datasets compared instantly by sophisticated software. So, the mutations in an individual tumour can be mapped and the relevant mRNA constructs made and inserted into a suitable vector within days.
There are all sorts of technical issues in the quest for a perfect vaccine. Naked mRNA injected into muscle, skin, or nodes would be the simplest route. This would allow the dendritic cells to ingest the RNA, express it, and induce potent anti-tumour T cell responses. But naked RNA is easily degraded by natural enzymes so carrier systems with polymers of peptides or lipids may enhance antigen production.
Currently the most promising vehicles seem to be lipoplexes. Negatively charged mRNA and positively charged cationic lipids form natural complexes for injection. BioNTech pioneered a four-antigen complex (BNT 111) in 50 patients with metastatic melanoma with 35% achieving a partial response last year.
But it is the bespoke vaccines created for individual patients that are most likely to have the greatest success and revolutionise the field, and certainly capture the imagination. In June last year, startling data were presented at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago. Sixteen pancreatic cancer patients were given a personalised vaccine around 9 weeks after surgery at Memorial Hospital, New York. In eight of the patients, the vaccine did not elicit an effective immune response and their cancers returned. But the other eight remained cancer-free 18 months later. In December, Moderna reported positive results of this technology in a trial of stage III melanoma using 34 personal neoantigens. There was a 44% reduction of cancer returning compared to a control, unimmunised group.
This technology will create a new way of working for big pharma, which so far has stuck to selling powders in bottles. A whole new service culture will be needed – pathology services will need to curate and supply fresh tissue; hospital pharmacies will need to engage with new organisations to deliver bespoke vaccines and provide them to oncologists ready for injection. And there are many variables in terms of dose, timing, the use of checkpoint inhibitors to take the brakes off the immune response and, of course, the addition of more conventional radiotherapy and chemotherapy.
Professor Justin Stebbing from Cambridge writing in The Conversation said recently: "Advances in medicine are usually made in small steps, but mRNA vaccines – a new form of personalised, targeted medicine – could be a giant leap, just like the anti-PD1 or anti-PDL1 immunotherapies. It's exciting that the UK will be central to that journey, to help turn cancer not only into a chronic disease we can live with but one we can cure".
But not everybody is so positive. Professor Gus Dalgleish from St George's, London who is also principal of the Institute of Cancer Vaccines and Immunotherapy (ICVI) told me: "Having conducted many different vaccine trials, I feel that correcting the innate immune response suppressed by the presence of a cancer is more important than identifying specific antigens. Indeed, having reviewed many different candidates, the non-specific mycobacterium-based vaccines such as Immodulon are the most effective. mRNA vaccines may not be the only holy grail."
What Will the Future Look Like?
The cancer patient of 2040 will have minimally invasive robotic surgery to remove their primary cancer and a full staging process by sophisticated imaging. Radiotherapy using artificial intelligence to optimise the treatment plan will be given if there is significant risk of local recurrence. Novel radiation delivery modalities such as proton beam therapy and the MR-LINAC will be used to dose spare critical surrounding normal tissue so reducing long term toxicity. Those patients who present with metastatic disease already detected will go straight to systemic treatment just as today.
Molecular analysis of the removed cancer will determine the risk of systemic spread. If high, a programme of chemo-immunotherapy will be triggered. The individual pattern of antigen expression on the tumour will be evaluated by robotic analysis and an AI generated series of mRNA sequences encoding the relevant epitopes generated. These will be taken from the curated repository and delivered in a suitable form for injection by the oncologist.
The service providers will be different from today. There will be local collectors of tissue and central laboratories run by today's big pharma. The latter will process and analyse tissue from patients sent by the local labs. Robots will identify and insert the appropriate sequences into vectors ready for injection into individuals. Maybe they will already be synthesised and stored in vials rather like the jars in an old-fashioned chemist's shop. Everything will be based on recurrence risk assessment. The oncologist will be provided with a printout of the sequences for injection and a week afterwards a blood sample will be taken to verify a successful immune response to the translated epitopes.
In addition, checkpoint inhibitors and non-specific immunostimulants may be given to enhance the immune response to the mRNA vaccination. For some patients' chemotherapy may also be given to enhance natural tumour antigen release. And single fraction, high ultra-high dose rate radiotherapy (FLASH) may be delivered to the tumour bed for the same reason. Everything will be personalised using novel algorithms.
Who knows whether these predictions are correct? The one certainty is that we are witnessing amazing developments in our understanding of the molecular basis of cancer and the body's reaction to it. Novel therapeutic approaches will almost certainly follow but there may well be some surprises.