New Delhi: Pancreatic cancer is considered among the deadliest forms of malignancies, killing over 87 percent of those afflicted within five years of diagnosis. A personalised mRNA vaccine to treat the condition—seen as a potential breakthrough against the lethal cancer—has fuelled hopes where none existed before.
The results from the Phase 1 clinical trial in the US—published in the science journal Nature last month—show that the experimental cancer vaccine, named autogene cevumeran, activated tumour-specific immune cells, which persisted in the body up to nearly four years after treatment in some patients.
Additionally, patients with a vaccine-induced immune response had a reduced risk of cancer recurrence at a three-year follow-up compared with patients whose immune systems did not respond to the vaccine.
Sponsored by biotechnology firms BioNTech and Genentech, cancer researchers associated with the Olayan Centre for Cancer at the New York-based Memorial Sloan Kettering (MSK) Cancer Center carried out the trial.
Autogene cevumeran, though called a vaccine because it activates specific immunity cells to fight the cancer cells, is designed to treat pancreatic cancer or pancreatic ductal adenocarcinoma (PDAC) by delivering proteins found in cancer or neoantigens into the body as a way to train the immune system to recognise cancer cells as foreign.
Neoantigens are unique cancer-specific proteins arising from genetic mutations within tumours.
“The latest data from the phase 1 trial are encouraging,” Dr Vinod Balachandran, the principal investigator of the trial and senior author of the publication, said in a release issued by MSK last month. “They suggest this investigational therapeutic mRNA vaccine can mobilise anti-tumour T-cells that may recognise pancreatic cancers as foreign, potentially years after vaccination.”
The development has oncologists hopeful back home, as well.
“By teaching the immune system to recognise and attack these neoantigens, mRNA vaccines could potentially overcome pancreatic cancer immune evasion mechanisms,” Dr Sewanti Limaye, the director of medical and precision oncology at Sir H.N. Reliance Foundation Hospital in Mumbai, told ThePrint.
The latest trial, she added, showed promising results, with patients demonstrating robust immune responses and some evidence of tumour regression.
Complex science, promising results
A small group of 16 MSK patients, each of whom had had tumours removed, received personalised versions of the vaccine based on the specifics of their tumour. They also received an immunotherapy drug called atezolizumab and a chemotherapy regimen called mFOLFIRINOX.
Early immunological and clinical results from the trial, whose results came out two years ago, showed that the treatment was generally well tolerated and stimulated an immune response in the vaccine responders, correlating with a delayed recurrence at a 1.5-year median follow-up, compared with the non-responders.
Now, the results at a three-year median follow-up have revealed that the investigational cancer vaccine activated a T-cell response in half of the patients (responders), and the response correlated with a delayed cancer recurrence, at three-year post-treatment follow-up, compared with non-responders.
T-cells are a type of white blood cell that helps protect the body from infection and diseases and can destroy pathogenic and cancerous cells. The experimental vaccine activates long-lasting CD8+ T-cells that recognise and attack cancer cells. The CD8+ T-cells made up as much as 10 percent of all blood T-cells and remained active over time, explained Dr Moushumi Suryavanshi, the molecular biologist, researcher and scientist at Amrita Institute of Medical Sciences and Research Center in Faridabad.
Patients who responded to the vaccine had a longer recurrence-free survival than those who did not respond. The median recurrence-free survival for responders is still unknown as they are still surviving. For non-responders, it is just 13.4 months.
And though the researchers do not yet know if the vaccine caused the delay in cancer recurrence, investigating the question is a goal of an ongoing randomised Phase 2 clinical trial, which has begun in 260 patients across several sites globally.
According to the Phase 1 trial, of the eight patients whose immune systems responded to the vaccine during the study period, six had not seen their cancers return during the follow-up period. The other two patients relapsed, and they showed weaker vaccine-induced T-cell activity compared with other responders.
Studying the tissue and blood from the patients (responders) before and after the vaccine administration, the researchers found that the vaccine stimulated a majority of new T-cells, which remained undetectable before vaccination.
Moreover, the vaccine-induced T-cells persisted beyond two years post-vaccination, maintaining anti-cancer function in some patients.
“Given the data from our Phase 1 trial, we are excited to evaluate therapeutic mRNA cancer vaccines in more pancreatic cancer patients,” Dr Balachandran said.
The now-started Phase 2 trial will assess whether the mRNA vaccine approach is better than the current standard treatment, which includes surgery followed by chemotherapy for pancreatic cancer patients.
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Designing a personalised vaccine
As part of the trial, after a patient had a pancreatic tumour surgically removed, the tumour was genetically sequenced to look for up to 20 mutations and, hence, have the highest likelihood to produce the best neoantigens by looking the most foreign to the immune system.
The cancer vaccine candidate gets manufactured with messenger RNA (mRNA)—single-stranded ribonucleic acid in living cells specific to the neoantigens found in the tumour of any individual. Any mRNA vaccine uses mRNA to prompt the body to produce proteins, which help fight foreign or unwanted invaders such as viruses or tumour cells.
According to scientists, the process of designing and manufacturing individualised vaccines for cancer treatment is more complex than making a preventive vaccine for an infectious disease, where each vaccine is the same and manufactured in large batches.
The individualised therapeutic mRNA cancer vaccine should be personalised to each patient’s tumour. To do that, researchers take a sample from the tumour by removing it during the required cancer surgery before shipping it to BioNTech in Germany. The next step is to analyse the tumour sample and design and manufacture the cancer vaccine candidate, which goes back to New York and other trial centres, where the investigational treatment is under research. Later, the vaccine is infused into the patient’s bloodstream.
In some patients, it may result in immune cells called dendritic cells—a special type of immune cell found in tissues such as the skin—which, to make the neoantigen proteins, boost immune responses by showing antigens on the surface of other cells of the immune system.
In some cases, the dendritic cells, additionally, may train the rest of the immune system, including the T-cells, to recognise and attack tumour cells expressing the same proteins. With the T-cells on high alert to destroy cells bearing these proteins, the cancer may have a lower chance of returning.
Hope for a new pathway
According to Globocan 2022, released by the World Health Organisation-International Agency for Research in Cancer (WHO-IARC), there were 5,10,992 cases of pancreatic cancer in 2022. The same cancer is ranked 12th among various forms of cancer worldwide. However, in terms of mortality, the malignancy killed 4,67,409 patients that year, emerging as the 6th most fatal cancer globally.
In India that year, 13,661 pancreatic cancer cases and 12,759 deaths were reported.
As PDAC is notorious for its aggressive nature and poor prognosis—mainly due to its ability to evade immune detection—the promising results from the Phase 1 trial in the US have been considered a breakthrough.
Dr Limaye underlined how Dr Balachandran’s approach represents a paradigm shift in cancer immunotherapy, suggesting that mRNA technology—already proven in COVID-19 vaccines—promised to revolutionise the fight against pancreatic cancer, offering hope for more effective, targeted therapies.
“A prominent figure in cancer research, Dr Balachandran, has been pioneering the exploration of mRNA vaccine technology in pancreatic cancer treatment. His work focuses on leveraging the immune system’s ability to target specific cancer cells through personalised vaccines,” she pointed out.
Dr Suryavanshi said this might only be the beginning in personalised cancer treatment.
“RNA cancer vaccines could open doors to treating other lethal cancers, transforming the future of oncology. If further studies confirm these findings, personalised cancer vaccines may soon offer patients longer survival and better outcomes, bringing hope where little existed before,” said the oncologist-researcher.
(Edited by Madhurita Goswami)
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Hi there,
Thank you for sharing this article. It is interesting! Can I request the manuscript or other details from the researchers .