Personalised mRNA cancer vaccine prolongs survival in melanoma


Personalised mRNA-based cancer vaccine mRNA-4157/V940, in combination with the immune checkpoint inhibitor pembrolizumab (Keytruda) improved recurrence-free survival (RFS) compared with pembrolizumab alone in patients with high-risk melanoma.

The clinical benefit was observed regardless of the tumour mutational burden (TMB) status, according to results from the Phase IIb KEYNOTE-942 clinical trial presented at the AACR Annual Meeting 2023, held April 14-19.

“Vaccine strategies over the last 25 years attempted to induce immune responses against tumour-associated antigens that are not absolutely specific to the tumour,” said presenting author Jeffrey Weber, Deputy Director of the NYU Langone Perlmutter Cancer Center and Laura and Isaac Perlmutter Professor of Oncology at NYU Grossman School of Medicine.

“More recent cancer vaccine approaches have focused on targeting neoantigens originated from individual tumour mutations, which are unique to cancer cells.”

mRNA-4157/V940 is a novel mRNA-based personalized cancer vaccine that encodes up to 34 patient-specific tumour neoantigens. In addition to encoding the target antigens, mRNA vaccines also provide adjuvant properties that amplify the immune response.

The randomised KEYNOTE-942 trial assessed the efficacy of mRNA-4157/V940 in prolonging RFS in patients with resected, stages IIIB/IIIC/IIID and IV melanoma when given in combination with pembrolizumab, the standard-of-care adjuvant therapy in this patient population.

According to the results of the primary trial analysis, after 18 months, the RFS was 78.6% in the combination arm and 62.2% in the pembrolizumab arm, corresponding to a 44% reduction in the risk of recurrence or death in patients who received both mRNA-4157/V940 and pembrolizumab.

“For the first time in a randomised study with a control arm, the addition of an mRNA neoantigen vaccine appeared to augment the benefit of PD-1 blockade, without adding significant high-grade toxicity,” said Weber. “This study is extraordinarily important, because it gives hope that this novel strategy will provide clinical benefit.”

Tumour mutational burden

In an additional analysis of KEYNOTE-942, baseline biopsies from the trial participants were assessed for TMB and how it relates to RFS across the study arms. The threshold used to define TMB-high status for the analysis was 10 mutations per megabase.

“We focused on the TMB because it has been shown to be a predictor of response to immune checkpoint inhibitor therapy and it is relevant to a neoantigen vaccine product – theoretically, if you have a higher TMB, there will be more neoepitopes to target,” said presenting author Ryan Sullivan, Associate Director of the Melanoma Program at Mass General Cancer Center and associate professor at Harvard Medical School.

The vaccine-pembrolizumab combination led to a similar reduction in the risk of recurrence or death in patients with high and low TMB (35% and 41%, respectively).

“Patients who were treated with the combination of vaccine and pembrolizumab had better outcomes than those treated with just pembrolizumab, independent of their TMB,” Sullivan said.

According to Sullivan, this suggests that an algorithm efficient in choosing the target neoantigens can potentially enable the vaccine to induce a robust immune response regardless of the TMB. “There likely is a certain TMB threshold below which our ability to successfully create a neoantigen vaccine is reduced, but our findings indicate that, above that threshold, the benefit of adding vaccination to pembrolizumab was similar regardless of the TMB.”

The association between this treatment approach and TMB will be further explored in upcoming studies. Additional analyses are ongoing to identify biomarkers potentially associated with better outcomes, including gene expression profiles and PD-L1 expression.

“The relevance of this study is the impact it could have not just for melanoma patients but for other cancers as well,” Sullivan said. “From a general cancer therapeutic standpoint, this is a potential major breakthrough.”

Limitations of the trial

According to Weber, one limitation of the KEYNOTE-942 trial is that, although randomised, it is a Phase IIb study with modest statistical power. “Overall, it is a small number of patients, and one has to be cautious with the interpretation of the results,” Weber said. “A larger, Phase III randomised study to confirm our findings will begin soon.”

Additional limitations include relatively short follow-up time and some setbacks, including cancer vaccine shortage, during the Covid-19 pandemic.

According to Sullivan, a technical limitation of the neoantigen vaccine approach is that it is based on DNA and RNA sequencing of tumour tissue, therefore it may not be applicable to patients with earlier-stage disease, whose tumours may be smaller and not provide enough tissue.

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