Personalised mRNA vaccine shows promise in delaying pancreatic ductal adenocarcinoma relapse

A new study published in Nature Journal shows that adjuvant autogene cevumeran, a personalized mRNA neoantigen vaccine, in combination with atezolizumab and mFOLFIRINOX induces significant T-cell activity in patients with surgically resected pancreatic ductal adenocarcinoma (PDAC), It has been shown to correlate with late recurrence.

PDAC is the third leading cause of cancer death in the United States and the seventh leading cause of death worldwide. PDAC is largely insensitive to immune checkpoint inhibitors. Part of this insensitivity is due to the fact that PDAC has a low mutation rate and produces few neoantigens. Therefore, this study was conducted to test the efficacy of adjuvant atezolizumab on PDAC. Here, researchers tested a real-time mRNA neoantigen vaccine from surgically resected PDAC tumors in a phase I trial of an adjuvanted autogene cevumeran, a personalized neoantigen vaccine based on uridine-mRNA lipoplex nanoparticles. Synthesized. After surgery, atezolizumab (anti-PD-L1 immunotherapy), autogene cevumeran (up to 20 neoantigens per patient), and a modified version of four-drug chemotherapy. Endpoints included vaccine-induced neoantigen-specific T cells using high-threshold testing, 18-month recurrence-free survival, and oncological feasibility.

The key findings of this study were:

1. Sixteen patients were treated with atezolizumab and autogene cevumeran, followed by 15 patients with mFOLFIRINOX. autogene cevumeran was administered within 3 days of its scheduled time, was well tolerated, and induced highly potent de novo neoantigen-specific T cells in 8 of 16 patients, half of whom received multiple neo-vaccines.

2. Targeted antigens. Using a novel mathematical strategy for tracking T cell clones (CloneTrack) and a functional test, vaccine-activated T cells represent up to 10% of all vaccine-reactivated T cells in the blood. found to occupy Booster and long-lived multifunctional neoantigens containing specific effector CD8+ T cells.

3. At an average follow-up of 18 months, patients with vaccinated T cells (responders) compared with patients without vaccinated T cells (non-responders; 13.4 months, P = ) , showed a longer median recurrence-free survival (not reached). 0.003).

4. Responders and non-responders developed equivalent immunity to concurrent, unrelated mRNA vaccines against SARS-CoV-2, so differences in patient immune fitness did not distort this association.

Reference:

Rojas, L. A., Sethna, Z., Soares, K. C., Olcese, C., Pang, N., Patterson, E., Lihm, J., Ceglia, N., Guasp, P., Chu, A., Yu, R., Chandra, A. K., Waters, T., Ruan, J., Amisaki, M., Zebboudj, A., Odgerel, Z., Payne, G., Derhovanessian, E., … Balachandran, V. P. (2023). Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. In Nature. Springer Science and Business Media LLC. https://doi.org/10.1038/s41586-023-06063-y