How mRNA vaccines could beat pancreatic cancer

Article by Adam Green, freelance journalist

Fighting the deadliest of cancers

The outlook for a patient with pancreatic cancer is bleak. The disease is often caught late and tends to be highly aggressive, reducing treatment options. Standard therapies are gruelling and, for many patients, extend life only modestly. Where surgery is possible, it offers the only realistic chance of a cure, but even then, many patients experience recurrence within less than a year. Nine out of ten people diagnosed die within 5 years.

Shivan Sivakumar, associate professor in oncology at the University of Birmingham, was drawn to the field precisely because it is “probably the worst common cancer in humans” and has so far proven resistant to effective therapeutic intervention. He is hopeful that a new trial leveraging mRNA, the technique that powered Covid-19 vaccines, could be deployed to fight the grimmest of cancers.

The University of Birmingham is working with University Hospitals Birmingham NHS Trust (UHB) in Europe’s first site to recruit patients to an investigational mRNA vaccine trial for pancreatic ductal adenocarcinoma (PDAC), the most common type. The trial is both scientifically and logistically ambitious, tackling one of the toughest cancers by deploying an emerging technique that primes the patient’s immune system to fight back. But delivering the trial requires an ecosystem of tightly linked capabilities that few universities can match.

Scientifically and logistically ambitious

mRNA vaccine research builds upon a growing body of evidence suggesting that the immune system can, in some patients, recognise and respond to cancer cells. Sivakumar explains that research into long-term survivors of pancreatic cancer shows they had one thing in common; their immune system appeared to have generated an immune response to the cancer cells.

This matters because cancer cells are notorious for outsmarting the body’s natural immune response and proliferating unchecked. Because tumour cells look familiar enough to avoid immune system attack, they evade the body’s built-in defences. This has always been one of the most persistent challenges in fighting cancer. Recent studies suggest not only that mRNA vaccines can induce an antigen-specific immune response, but that this immune ‘memory’ persists to prevent longer-term recurrence.

Training the immune system to spot cancer cells

If antigens related to cancer could be engineered to be distinguishable from the body’s own proteins, cancer cells would lose their ability to evade detection and would be destroyed by the immune response. “What the vaccine is trying to do is to induce an immune response”, says Sivakumar.

All cancers arise from genetic mutations. In the case of PDAC, 92% of tumours show a DNA mutation in the K-Ras gene. In a normal cell, this gene is responsible for regulating cell growth signals. If this ‘switch’ is mutated it can become stuck like a jammed accelerator pedal. In these circumstances cells will continue to replicate. Uncontrolled cell proliferation causes tumours to develop. K-Ras is often considered to be the driver of pancreatic cancer, but has hitherto been thought of as untreatable because the specific mutations vary from person to person. But according to Dr Sivakumar “K-Ras is now able to be drugged” for the first time through mRNA vaccination.

To better understand how this technology works, it is helpful to understand how mRNA functions in normal cell signalling. Essentially, mRNA is a short-lived set of instructions. It ‘reads’ the genetic material encoded in DNA and acts as a temporary messenger, travelling to the parts of the cell where proteins are made.

mRNA vaccines borrow this biology to deliver a short-lived script, which tells cells to create a harmless fragment of a particular target protein. In the PDAC mRNA vaccine, this fragment codes for a protein fragment (‘neo-antigen’) that is specific to the tumour. These fragments are recognised by the immune system as abnormal, leading to an immune response to all cells carrying the same target neo-antigens. Any residual cancer cells left behind after surgery that would normally seed recurrence, would be destroyed. Essentially, the PDAC mRNA vaccine turns a patient’s own tumour into a set of instructions and the trial will test whether this will translate into an immune system adaptation that provides a measurable prevention of recurrence.

Researchers believe the vaccine will help the immune system eliminate remaining cancer cells and lower the risk of the disease returning. The trial involves post-operative pancreatic cancer patients. Following surgery, patients will receive either standard chemotherapy alone or chemotherapy plus the personalised mRNA vaccine.

The vaccine journey

For patients on the mRNA arm of the trial, samples of diseased tissue are extracted from their tumour following surgery. These samples are currently sent to Germany, where cancer cell genetic material is sequenced to identify the specific mutations that led to the cancer. This sequence is encoded into a bespoke mRNA “recipe”. The engineered mRNA is packaged with lipid particles and injected. It can then provide the instructions for the cell to generate fragments of tumour-specific targets, which the immune system learns to recognise and attack.

This is one of the key differences between Covid-19 mRNA vaccines and cancer vaccines. The former could be standardised and manufactured at scale because the viral target fragment is the same, whereas cancer vaccines must be made bespoke. Each tumour has a unique genetic profile, and so personalised vaccines cannot be produced off-the-shelf. They are also only possible when a person already has cancer.

Ultimately, the purpose of personalised mRNA vaccines is to stop pancreatic cancer in people who have undergone surgery, chemotherapy and months of uncertainty and suffering. Success will be measured in fewer relapses, longer survival and enhanced quality of life.

Birmingham: ideally placed to deliver this trial

The academic-clinical partnership within Birmingham makes it well-suited to deliver what is, even by the industry’s standards, a highly ambitious and challenging trial. It requires rapid transportation of tissue, sequencing, target selection, manufacture and careful dosing and monitoring.

Birmingham is one of Europe’s leading hubs for cancer research and clinical trials, aligned with the NHS’s Cancer Vaccine Launch Pad to enhance coordination, recruitment and sponsorship to expedite access to mRNA vaccine trials for people with cancer. As one of the UK’s regional specialist pancreatic surgical centres, Birmingham can coordinate care for patients drawn from a wide geographical area, creating the infrastructure needed to support complex early-phase trials of this kind.

University Hospitals Birmingham NHS Trust already treats the UK’s highest number of pancreatic cancers, which will support trial recruitment and the capacity to handle samples. The fast-track pathway for pancreatic cancer surgery means that vital time can be saved before the disease has become too aggressive to manage.

Proximity matters. Sivakumar explains that in other centres people could be waiting two or three months, but in Birmingham “we’re operating on you and recruiting you to a trial almost within days”. Longer term, there are ambitions to bring this capability closer to home and speed up the “tumour-to-vaccine” journey.

There are plans to build clean room facilities at the University's Precision Health Technology Accelerator based at Birmingham Health Innovation Campus, located close to both the surgical team at the Birmingham Queen Elizabeth Hospital and the University of Birmingham’s research facilities. This will allow for near-patient bio-manufacturing of advanced therapies, such as the mRNA vaccine, which would allow all the work to take place in Birmingham, getting treatment to patients sooner. This is part of a wider vision in which Birmingham’s Health and Life Sciences District will power the research and development breakthroughs needed to support the UK government’s long-term strategy to foster health system resilience through domestic bio-manufacturing and to strengthen national capabilities in drug discovery.