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HomeOncologymRNA vaccine can recognise neoantigens in pancreatic cancers – US study

mRNA vaccine can recognise neoantigens in pancreatic cancers – US study

BioNTech has announced initial data from an ongoing study which shows that mRNA-based individualised neoantigen specific immunotherapy (iNeST) vaccines can be used to stimulate T cells to recognise neoantigens in pancreatic cancer patients.

The data from the investigator-initiated first-in-human phase I study evaluating the safety and tolerability of the mRNA-based individualised neoantigen specific immunotherapy (iNeST) autogene cevumeran (also known as BNT122, RO7198457) in combination with anti-PD-L1 immune checkpoint inhibitor atezolizumab and chemotherapy in patients with resected pancreatic ductal adenocarcinoma (PDAC).

The preliminary results showed a favourable safety profile, as well as encouraging signs of clinical activity.

The data include a total of 19 patients who underwent surgery and received atezolizumab. Of these patients, 16 (84%) received autogene cevumeran at 9.4 weeks after surgery. The preliminary data readout from these 16 vaccinated patients revealed that autogene cevumeran in combination with atezolizumab was well-tolerated. Only one of 16 patients (6%) developed a vaccine-related Grade 3 fever and hypertension. No other Grade 3 or higher adverse events were observed.

In addition, the treatment induced de-novo, neoantigen-specific T cell response in half of these patients, from undetectable levels to large fractions of all blood T cells (median 2.9 percent). At an early median follow-up of 18 months, the eight patients with de-novo immune response had a significantly longer recurrence-free survival (RFS) as compared to the eight without vaccine-induced immune responses (median not reached versus 13.4 months, respectively).

Based on these data, BioNTech and Genentech are planning a randomised study to further evaluate the efficacy and safety of autogene cevumeran in combination with atezolizumab and chemotherapy in patients with resected PDAC.

“With only under five percent of patients responding to current treatment options, PDAC is one of the highest unmet medical need cancers,” commented Professor Dr Özlem Türeci, co-founder and chief medical officer at BioNTech. “We are committed to take up this challenge by leveraging our long-standing research in cancer vaccinology and are trying to break new ground in the treatment of such hard-to-treat tumours.”

The investigator-initiated, single-centre, Phase I trial (NCT04161755) was designed to evaluate the treatment of the companies’ individualised immunotherapy candidate autogene cevumeran in combination with the anti-PDL-1 immune checkpoint inhibitor atezolizumab as an add-on to the standard-of-care regimen with adjuvant chemotherapy mFOLFIRINOX in patients with resected PDACs. The primary objective of the study is to assess the safety. Secondary objectives include the efficacy of the treatment measured as the 18-month RFS, the immunogenicity as well as the feasibility of the treatment regimen.

“Our research, and now the results from this study, show the immune system can recognise neoantigens in pancreatic cancer, and that we can use mRNA vaccines to stimulate T cells to recognise neoantigens in pancreatic cancer patients,” stated Dr Vinod Balachandran, surgeon-scientist at Memorial Sloan Kettering Cancer Centre and principal investigator of the study. “We now look forward to further investigating these results in a larger randomised trial.”

Study details

Phase I trial of adjuvant autogene cevumeran, an individualised mRNA neoantigen vaccine, for pancreatic ductal adenocarcinoma.

Vinod P. Balachandran, Luis A. Rojas, Zachary Sethna, Kevin Soares, Evelyna Derhovanessian, Felicitas Mueller, Mahesh Yadav, Olca Basturk, Mithat Gonen, Alice Chia-chi Wei, Michael Ian D'Angelica, T. Peter Kingham, Benjamin Greenbaum, Taha Merghoub, William R. Jarnagin, Jeffrey A. Drebin, Ugur Sahin, Oezlem Tuereci, Jedd D. Wolchok, Eileen Mary O'Reilly

Background
Pancreas ductal adenocarcinoma (PDAC) is a lethal cancer that claims ̃90% of patients in <24 months of diagnosis. PDAC is also refractory to immunotherapy as most tumours exhibit an immune excluded/desert phenotype. However, although characterised by low mutation rates, most PDACs harbour mutations that can generate immunogenic neoantigens. Here, we report the results of a phase-I trial of autogene cevumeran, a systemic RNA-lipoplex individualised neoantigen-specific immunotherapy (iNeST) vaccine, to stimulate immunity against neoantigens in resected PDAC patients.

Methods
We conducted an investigator-initiated, single-centre, phase-I trial of adjuvant autogene cevumeran containing up to 20 neoantigens in each individualised vaccine, identified from resected PDACs using real-time next generation sequencing and bioinformatic neoantigen discovery. Following surgery, patients received atezolizumab (1 dose; week 6), autogene cevumeran (8 weekly doses starting week 9; doses 9,10 – weeks 17, 46), and modified (m) FOLFIRINOX (12 cycles; starting week 21). Primary endpoint: safety. Other endpoints: feasibility (actual vs. target treatment time), vaccine response (responder = positivity by two independent blood assays: IFNg ELISpot and T cell clonal expansion), and recurrence-free survival (RFS). Target accrual: n=20.

Results
n=19 patients underwent surgery and received atezolizumab at 6.3 weeks (median; 95% CI 6.0–6.57) after surgery with no ≥ grade 3 (Gr3) adverse events. n=16/19 patients (84%) received autogene cevumeran at 9.4 weeks (median; 95% CI 9–10) after surgery. n=1/19 (5%) had insufficient neoantigens for vaccine manufacture. n=1/16 (6%) developed a vaccine-related Gr3 fever and hypertension. n=15/16 vaccinated patients (94%) received mFOLFIRINOX (median 12 cycles; 95% CI 7–12). Autogene cevumeran expanded polyclonal (median 7.5 clones, 95% CI 2–28), IFNg-producing neoantigen-specific CD8+ T cells in 50% (n=8/16) of patients from undetectable levels to large fractions (median 2.9%, Table) of all blood T cells. At an early median follow-up of 15 months, vaccine responders (n=8) had a longer RFS vs. non-responders (n=8) (median not reached vs. 13.7 months, HR 0.08, 95% CI 0.01-0.5, P = 0.007).

Conclusions
Autogene cevumeran is safe, feasibly manufactured in a clinically relevant timeframe, and immunogenic in PDAC. Vaccine induced neoantigen-specific immunity preliminarily correlates with improved PDAC outcome. Further clinical trials in PDAC are warranted. (This imCORE Network project was funded by Genentech Inc and BioNTech; additional funding from Stand Up To Cancer, Lustgarten Foundation)

 

ASCO presentation (Open access)

 

European Pharmaceutical Review

 

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