mRNA Vaccine Autogene Cevumeran Plus Atezolizumab and Chemotherapy Displays Early Efficacy in PDAC

Adjuvant treatment with the individualized RNA neoantigen vaccine autogene cevumeran in combination with atezolizumab (Tecentriq) and chemotherapy induced notable T-cell activity that could be correlated with delayed recurrence in patients with pancreatic ductal adenocarcinoma (PDAC), according to findings from a phase 1 trial (NCT04161755) published in Nature.¹

Sixteen patients received the anti–PD-L1 antibody atezolizumab and autogene cevumeran, 15 of whom were subsequently treated with mFOLFIRINOX. The vaccine was found to be tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 patients. Additionally, the vaccine-expanded T cells made up as much as 10% of all blood T cells, were able to be reexpanded with a booster, and contained long-lived polyfunctional neoantigen-specific effector CD8-positive T cells. At a median follow-up of 18 months, among patients who were biomarker evaluable, the median recurrence-free survival (RFS) was not yet reached (NR) for vaccine responders (n = 8) compared with 13.4 months among non-responders (n = 8; HR, 0.08; 95% CI, 0.01-0.4; P = .003).

“These exciting results indicate we may someday be able to use vaccines as a therapy against pancreatic cancer,” Vinod P. Balachandran, MD, an assistant attending surgeon at Memorial Sloan Kettering Cancer Center in New York, New York, and a coauthor of the study, said in a news release. “The evidence supports our strategy to tailor each vaccine to each patient’s tumor.”²

Autogene cevumeran is an mRNA vaccine that contains up to 20 major histocompatibility complex class I (MHCI) and MHC class II restricted neoantigens in lipoplex nanoparticles. The vaccine is delivered intravenously. Study authors hypothesized the vaccine could induce neoantigen-specific T cells in PDAC, eliminate micrometastases, and ultimately delay recurrence.1

To conduct their study, investigators enrolled a total of 34 patients with surgically resectable PDAC, an ECOG performance status of 1 or less, no distant metastases, and at least 5 neoantigens. Patients who received neoadjuvant therapy and those with metastatic, borderline or locally unresectable PDACs were excluded.

Eligible patients initially underwent open pancreaticoduodenectomy, or open or laparoscopic distal pancreatectomy and splenectomy. Following surgery, patients with pathologically confirmed PDAC with R0/R1 margins were included.

Atezolizumab, autogene cevumeran, and mFOLFIRINOX were given sequentially for investigators to measure how each agent modulated neoantigen-specific T cells. Benchmarked times were set after surgery to establish clinical feasibility: a single 1200-mg intravenous dose of atezolizumab on week 6; nine 25 µg intravenous doses of autogene cevumeran given as 7 weekly priming doses beginning on week 9, an eighth dose at week 17, and a ninth booster dose at week 46; and 12 cycles of mFOLFIRINOX beginning on week 21.

Study authors also developed the mathematical and immunological method CloneTrack to track T-cell clones and functional assays. CloneTrack uses T-cell receptor Vβ sequencing of peripheral blood samples before and after treatment to identify treatment-expanded high-magnitude T-cell clones.

The primary end point of the study was safety. Secondary end points consisted of 18-month RFS and 18-month overall survival (OS).

Twenty-eight patients underwent surgery, 19 received atezolizumab, and 16 subsequently were treated with autogene cevumeran. The 19 patients evaluable for safety displayed clinical characteristics common among patients with resectable PDAC.

No patients who received atezolizumab experienced grade 3 or higher adverse effects (AEs), with 1 patient who received autogene cevumeran experiencing grade 3 fever and hypertension. All patients who received the vaccine had grade 1 or 2 AEs.

Atezolizumab and autogene cevumeran were administered at median times within 1 and 3 days of respective benchmarked times; the median time to atezolizumab administration was 6.1 weeks (range, 4.3-7.9) and the median time to autogene cevumeran administration was 9.4 weeks (range, 7.4-11.0). One patient who received atezolizumab had insufficient neoantigens and thus did not have a vaccine manufactured. Of the patients who received the vaccine, 3 did not receive all 9 doses due to progression, death, or mFOLFIRINOX toxicity.

According to CloneTrack, vaccine-induced clonal expansion was present in all responders and 1 nonresponder. Among responders, autogene cevumeran expanded a median of 7.5 clones from undetectable levels to a median level of 2.8% of all blood T cells. Patients who received booster doses (n = 7) all experienced re-expanded identical primed clones.

Additional findings from a landmark analysis, which correlated RFS to response in patients who were recurrence-free when completing all 8 autogene cevumeran priming doses, showed that vaccine responders experienced a median RFS of NR compared with 11.0 months among 7 nonresponders (HR, 0.06; 95% CI, 0.008-0.4; P = .008). Responders also had persistently lower serum CA19-9 levels compared with nonresponders.

The 24-month OS rate was approximately 90% for all patients in the safety cohort. Autogene cevumeran was found to induce high-magnitude T-cell responses specific to 25 of 106 vaccine-encoded antigens in responders.

Investigators noted that their study was limited by the inability to detect differences in biomarkers of vaccine response. The trial also had a limited sample size and only enrolled white patients. Study authors stressed that future studies should test individualized mRNA neoantigen vaccines in a diverse population of patients with PDAC, with a faster time to adjuvant mFOLFIRINOX.

Regardless, their study showed that mRNA neoantigen vaccines can be personalized in 9 weeks and fully integrated into a standard clinical workflow following surgery, investigators wrote. The global follow-up randomized phase 2 IMCODE001 (NCT03815058) and BTN122 (NCT04486378) trials are currently recruiting patients.

“We will continue to analyze data from the pancreatic cancer trial so we can better understand what factors help the vaccine work in patients,” Balachandran said in the release. “Of course, we want to find out why some pancreatic cancer patients didn’t respond to the vaccine and find solutions to this problem.”²

References

1. Rojas LA, Sethna Z, Soares KC, et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature. Published online May 10, 2023. doi:10.1038/s41586-023-06063-y
2. MSK mRNA pancreatic cancer vaccine trial shows promising results. News release. May 10, 2023. Accessed May 12, 2023. https://www.mskcc.org/news/can-mrna-vaccines-fight-pancreatic-cancer-msk-clinical-researchers-are-trying-find-out