An article in Nature in May 2023 presents work from a collaboration between Genentech, Memorial Sloan Kettering Cancer Centre (MSKCC), and BioNTech. Dr Vinod P. Balachandran, surgeon-scientist at MSKCC has been working on pancreatic ductal adenocarcinoma (PDAC) for years in the hope of replicating the rare survival of some patients for others. Through a personalised RNA neoantigen approach, he may have finally found a route.
The article reports that PDAC is the “third leading cause of cancer death” in the US, and the seventh worldwide. Unfortunately, the survival rate of 12% has “remained largely stagnant for nearly 60 years” as incidence continues to grow.
“PDAC is projected to cause even greater global cancer deaths by 2025.”
Currently the only curative treatment is surgery, yet up to 90% of patients have disease recurrence at around 7-9 months and the 5-year survival is 8-10%.
“Radiation, biologics, and targeted therapies are also ineffective.”
Furthermore, PDACs are “almost completely insensitive to immune checkpoint inhibitors”. This is “partly attributed to the fact that PDACs have a low mutation rate”. They therefore generate few neoantigens, which mark the cancer as foreign to T cells. However, recent studies have shown that PDACs “harbour more neoantigens than previously predicted”, and studies of long-term survivors have suggested that “neoantigens may stimulate T cells in PDAC”.
Replicating survival traits
The authors state that, based on the observation that long-term survivors “mount spontaneous T cell responses” against “tumour-specific neoantigens not shared among patients”, they decided to investigate if “adjuvant individualised vaccines can stimulate neoantigen-specific T cells and provide clinical benefit”.
The known benefits of mRNA vaccine technology led the researchers to suggest that an effective mRNA vaccine could induce neoantigen-specific T cells in PDAC, eliminate micrometastases, and delay recurrence. To explore this, they conducted an investigator-initiated, Phase I clinical trial of sequential adjuvant atezolizumab (Genentech), autogene cevumeran restricted neoantigens in lipoplex nanoparticoles intravenously delivered, individualised NeoAntigen-Specific Therapy (iNeST), and mFOLFIRINOX in patients with surgically resectable PDAC.
A positive start
The study demonstrates that adjuvant autogene cevumeran, the individualised neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, in combination with atezolizumab and mFOLFIRINOX, is “safe, feasible, and generates substantial neoantigen-specific T cells in 50% of unselected patients with resectable PDAC”.
“Here, we provided evidence that despite the low mutation rate of PDAC, a mRNA vaccine can induce T cell activity against neoantigens in this cancer.”
The individualised mRNA cancer vaccines were tested in the adjuvant setting due to observations that vaccines against pathogens have “historically been most effective in preventative and not therapeutic settings”. From this the authors infer that “vaccine efficacy requires an optimally functioning host immune system”. However, in patients with advanced cancer, neoantigen vaccination is challenged by “global impairments in host immunity” and “knowledge gaps on neoantigen heterogeneity between tumours”. Therefore, the researchers recommend that vaccines are tested in patients with minimal residual disease.
Moving forward through challenges
The article shows that PDAC tumours do harbour neoantigens suitable for vaccines, and T cell can be generated in response to mRNA vaccines. Additionally, there is a correlation between vaccine-induced T cells and delayed cancer recurrence.
Although the trial was conceived in 2017, and began in December 2019, it encountered an enormous and familiar obstacle a few months in. Dr Balachandran told GEN that this “posed several unique challenges” such as “shutdowns and global supply chain disruptions”. Furthermore, the distraction presented by BioNTech’s task of manufacturing vaccines “to save the world” was another barrier to success. However, Dr Balachandran believes that intead of slowing the trial down, they were able to “accelerate it to complete it a full year ahead of schedule”.
‘We think this can hopefully speak to the idea that rapid custom cancer vaccination is feasible in the clinic.”
Dr Ira Mellman of Genentech admits that at the start, many people viewed the project as an “over-the-horizon or blue-sky thing”, with little expectation of success.
“Now, from two different sources that are totally independent, both using mRNA vaccines, they seem to have some rather significant glimmers of clinical benefit. Whether it’s the next big thing, I’m not prepared to say, but it could be.”
For more insights into therapeutic vaccine development, head to our therapeutic section to view previous articles.