Dr Stephen Huang and Mr James Huang take a look at the  promise of mRNA in personalised cancer treatment

Cancer treatment has made great strides over the past few decades. Once characterised by  gruesome operations, toxic chemotherapy and onerous radiotherapy, modern therapies now include robotic assisted operations, targeted chemotherapy and precision radiotherapy, all with improved efficiencies that have helped significantly boost treatment outcomes for patients.

The advent of immunotherapy, which really took off in the late 1970s with the discovery of the T-cell growth factor interleukin 2 (IL-2), has further improved the morbidity and mortality of many cancer patients by harnessing the body’s own defences to recognise and attack diseased cells. More recently, the coming together of certain emerging technologies, namely genomic sequencing and bioinformatics, has driven a further advance in the field – the use of mRNA (messenger ribonucleic acid) to treat cancers.

mRNA is a single-stranded molecule that carries genetic code from DNA in a cell’s nucleus to ribosomes in the cytoplasm where proteins are made. In humans, each molecule of mRNA encodes the information for one protein. mRNA medicines are essentially sets of instructions that direct cells in the body to make proteins to prevent or fight disease. Big pharma and its partners specialising in mRNA technology are now in a race to commercialise this promising therapy – which has several potential applications – in the coming years.

Cancer vaccines  

A leading strand of work on the therapeutic potential of mRNA is focused on the development of cancer vaccines. Using vaccines to treat cancers is very different from their traditional use to prevent and control infectious disease. Vaccines for immunisation are mass- produced, ie the same vaccine, targeting the same antigen(s), is used on a population-wide basis against each disease. Therapeutic cancer vaccines, on the other hand, can be truly personalised to treat a specified individual patient, and are designed to treat as opposed to prevent the disease.

How does it work?

Cancers are often caused by mutations triggered by various environmental and lifestyle factors. These mutations lead to the formation of new antigens (neo-antigens) unique to the tumour of the individual patient. These neo-antigens are ‘hidden’ from the patient’s immune system, which allow the tumour to grow unimpeded in the first place.

The process of developing a peronsalised cancer vaccine begins with extraction of DNA from an individual patient’s tumour cells, which is then sequenced and compared with germline DNA from normal cells. The comparison enables identification of the tumour’s mutations. Using proprietary algorithms, the immunogenic potential of the mutations is assessed and their neo-antigens are identified as developmental targets. Working ‘backwards’, the corresponding mRNAs are produced on a ‘per vaccine per person’ basis and injected into the patients. Once in the body, the mRNA is translated into a polypeptide that is processed into neo-antigens. The neo-antigens are then presented by dendritic cells (and other antigen-presenting cells) to helper T-cells and cytotoxic T-cells, which recognise and kill tumour cells.

Therefore, the mRNA does not ‘destroy’ the cancer cells itself, but encodes the production of proteins that enable the body’s own immune system to neutralise cancer cells while leaving the healthy cells alone; essentially turning the patient’s body into a factory able to produce protein-based drugs. Think of mRNA being a ‘medicine’ that is a set of instructions for the body to manufacture polypeptide therapies in vivo.

Big pharma’s focus

In an interview with Chemical & Engineering News, Moderna Therapeutics’ president Stephen Hoge recently said: “You could ultimately use mRNA to express any protein and perhaps treat almost any disease. It is almost limitless what it can do.” And now that many of the challenges of working with mRNA are starting to be addressed, pharma’s interest in the field is gaining momentum.

Across the Atlantic, Massachusetts, US-based Moderna is collaborating with Merck Sharp & Dohme using mRNA personalised cancer vaccines together with pembrolizumab (Keytruda) in resected solid tumours and melanoma. Earlier this year, the firms presented data at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting from an ongoing Phase I clinical study in patients with both adjuvant and unresected solid tumours, showing that the  mRNA personalised cancer vaccine mRNA-4157, given alone or in combination with Merck’s pembrolizumab, ‘was well-tolerated at all doses tested and elicited neoantigen-specific T-cell responses’. Moreover, there were no vaccine-related serious adverse events reported.

“For decades, the cancer community has been working on the concept of developing medicines that can be personalised down to the individual patient level,” said Howard Burris III, president, clinical operations & chief medical officer at Sarah Cannon Research Institute, and a principal investigator of the study. “We know that cancer mutations are rarely shared between patients, so it’s encouraging to see individualised, personalised cancer vaccines like mRNA-4157 eliciting immune responses.”

Moderna is also working with AstraZeneca, conducting trials which involve injecting mRNA vaccines via an intra-tumoural route into advanced solid tumors and lymphomas. One trial is assessing the safety and tolerability of escalating intratumoural doses of mRNA-2416 alone and in combination with intravenously administered flat doses of AstraZeneca’s (Imfinzi) durvalumab in patients with relapsed/refractory solid tumour malignancies or lymphoma, as well as the objective response rate of mRNA-2416 alone or in combination with durvalumab in ovarian cancer.

The firm recently raised more than $600 million in the biotech industry’s largest IPO, thus valuing the company at a staggering $7.5 billion.

Elsewhere, Sanofi has strengthened its ties with Mainz, Germany-based specialist mRNA company BioNTech with an 80-million euro equity investment, following a 2015 deal which saw the French drugmaker pay $60 million upfront to co-develop five mRNA-based cancer immunotherapies. Under the plans, the two companies will co-develop and co-commercialise a cancer vaccine for solid tumours, moving rapidly from concept to clinical trials over a three-year period. BioNTech, which is reported to be worth 2 billion euros, is also in collaboration Genentech, running clinical trials in melanoma, head and neck and breast cancers.

Another German company, Tubingen-based CureVav, licensed exclusive global rights to its lung cancer mRNA vaccine candidate CV9202 to Boehringer Ingelheim back in 2014. In one recent Phase Ib study of the candidate (now called BI 1361849) in patients with Stage IV NSCLC, cellular and humoral immune responses were observed in the majority of patients. Also, over half (52%) of evaluable patients had stable disease. A combination of BI 1361849 plus AstraZeneca’s durvalumab is currently being investigated with/without AstraZeneca’s tremelimumab in a Phase I/II trial in metastatic NSCLC patients, and future studies are being planned to investigate the mRNA vaccine in combination with other immunotherapies. Curevac has also partnered with the academic organisation HepaVac Consortium for liver cancer, and with Lilly in several cancers. The firm is reported to be worth 1 billion euros.

Future Expectations

All the above trials are still in Phase I/II of development and it is a testimony of the expectations of mRNA as a therapeutic cancer vaccine that investors and big pharma have valued the mRNA companies so highly.

Of course, the clinical performance and safety of mRNA vaccines remain unproven, and it is likely that it will be co-administered with other immunotherapies like monoclonal antibodies, while traditional treatment modalities like surgery, chemotherapy and radiotherapy will remain core to the oncologists. π