A personalised cancer vaccine improves the effectiveness of melanoma treatment, according to a phase 2 trial

What do you think of the article overall? Is it of good quality?

“Yes. It is a solid, clinically relevant piece of work and probably one of the most important studies to date on personalised neoantigen-based RNA vaccines. It has a sound methodological design, long-term follow-up and consistent clinical data. Furthermore, it provides mechanistic data that reinforces the biological rationale.”

How does it fit with the existing evidence, and what implications might it have?

“It fits very well with the idea that neoantigen-based vaccines can enhance the efficacy of anti-PD-1/PD-L1 antibodies by generating new anti-tumour T-cell responses. The key point is that, unlike other combinations of adjuvant immunotherapy, here we do observe a sustained reduction in the risk of relapse and metastasis. If the phase 3 clinical trial confirms these results, it could establish the first real standard for personalised RNA vaccines in oncology.”

Are there any significant limitations to bear in mind?

“Yes. The study remains relatively small, with few overall survival events, so the benefit in OS [overall survival] is not yet conclusive. The subgroup analyses are exploratory and some have very low statistical power. Furthermore, the mechanistic basis is indicative but indirect: it demonstrates peripheral clonal expansion, but not direct anti-tumour functional activity. Finally, melanoma is a particularly immunogenic tumour, so it is unclear whether these results can be extrapolated to other types of cancer.”

What do you think of the article overall? Is it of good quality?

“The quality is good, but above all, it is a robust article in that it demonstrates in a clinical trial something that was previously taken for granted: that the combination of a prior specific vaccine (in this case an mRNA vaccine) with an immune function enhancer (a checkpoint inhibitor, or ChkPI, in this case an anti-PD1) enhances the function of the latter, improving not only tumour clearance rates in more patients (49.1% for the ChkPI alone versus 68.8% for the combination), but also leading to an even greater increase in survival.”

How does this fit with existing evidence, and what implications might it have?

“It fits clearly with existing knowledge and should allow this combination to be introduced into treatment options for tumours, now in post-surgical melanoma, and also, possibly, in all tumours where the use of a ChkPI has shown benefit, although strictly speaking only the development of specific clinical trials will allow this to be demonstrated.”

Are there any significant limitations to bear in mind?

“The most significant limitation is that, beyond the concept which appears to hold potential, the demonstration has been carried out in a specific indication and its generalised extrapolation will take years, just as it has taken years for ChkPI indications to be approved in different circumstances and may still be pending in others (neoadjuvant therapy or with other combinations). Adding the vaccine (and this is a specific one, also limited to a few mRNAs) can be done in many other ways, not just with mRNA, which may prove to be better immunostimulants. And for each proposal, there will be evidence from the development of a trial.

In any case, the progress is evident and ‘further strengthens’ the use of immunotherapy, if that is even possible.”