mRNA Vaccine Promising for Pancreatic Cancer

A personalized mRNA vaccine, used in combination with an immune checkpoint inhibitor and chemotherapy after surgery, induced an immune response in half of treated patients with pancreatic ductal adenocarcinoma (PDAC), a small phase I trial showed.

At a median follow-up of 18 months after surgery, eight patients who had immune responses to autogene cevumeran had significantly longer recurrence-free survival (not reached) compared with a median of 13.4 months in the eight patients who had no response (HR 0.08, 95% CI 0.01-0.40, P=0.003), reported Vinod Balachandran, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues.

"Despite the limited sample size, these early results warrant larger studies of individualized mRNA neoantigen vaccines in PDAC," they wrote in Nature.

One patient also showed evidence of a vaccine-induced response in the liver after developing an unusual 7-mm lesion there. That growth disappeared on subsequent imaging, suggesting that "autogene cevumeran-expanded T cells may possess the capacity to eradicate micrometastases," Balachandran and team noted.

"As multiple immunotherapies have emerged for immune-inflamed tumors, there remains a need for new immunotherapies for the majority of patients with non-inflamed tumors (such as PDAC) that are largely insensitive to current immunotherapies," they wrote. "Here, we provided evidence that despite the low mutation rate of PDAC, a mRNA vaccine can induce T-cell activity against neoantigens in this cancer, a non-inflamed tumor with predominantly immune-excluded or desert phenotypes. Whether mRNA neoantigen vaccines can similarly activate T cells in other non-inflamed cancers should be more broadly tested."

In a "News and Views" article accompanying the study, Amanda Huff, PhD, and Neeha Zaidi, MD, both of Johns Hopkins University School of Medicine in Baltimore, wrote that the study authors "have established the feasibility of using mRNA-based neoantigen vaccines for pancreatic cancer, a disease that has previously been considered too aggressive for personalized therapeutics."

"The data also highlight the potency of pancreatic cancer neoantigens, giving hope that they might lead to the development of new treatment options for this refractory cancer," they added.

As Balachandran and colleagues pointed out, PDAC is the third leading cause of cancer death in the U.S., with incidence rates that are increasing, and a survival rate around 12%, which "has remained largely stagnant for nearly 60 years."

They also said that while surgery is the only curative treatment for the disease, almost 90% of patients have disease recurrence at a median of 7 to 9 months. Adjuvant multi-agent chemotherapies can delay recurrence in surgically resected PDAC, but nearly 80% of patients have disease recurrence by 14 months.

Furthermore, while the development of immune checkpoint inhibitors has revolutionized cancer treatment, most pancreatic cancers will not respond to these drugs. This is believed to be due to the fact that PDACs generate lower levels of neoantigens -- the mutation-generated proteins that mark cancers as foreign to T cells -- and are less likely to activate a strong immune response.

However, previous studies -- including research published by Balachandran and colleagues in 2017 -- demonstrated that long-term survivors of PDAC produce spontaneous T-cell responses against tumor-specific neoantigens.

Thus, they hypothesized that developing a vaccine that encodes neoantigens specific to individual patients "would induce neoantigen-specific T cells in PDAC, eliminate micrometastases and delay recurrence."

In this trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, the investigators synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumors. After surgery, they sequentially administered a single dose of the anti-PD-L1 immunotherapy atezolizumab (Tecentriq), autogene cevumeran (a maximum of 20 neoantigens per patient), and modified FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin).

From December 2019 to August 2021, Balachandran and colleagues enrolled 34 patients in the trial, 28 of whom underwent surgery. Nineteen patients were treated with atezolizumab, and 16 received subsequent autogene cevumeran; 15 of the 16 also received modified FOLFIRINOX.

Of the 16 patients who received the vaccine, mean age was 71-72, all were white, and they were split evenly by sex.

Among the safety cohorts -- the 19 patients treated with atezolizumab and the 16 treated with autogene cevumeran -- no patients had grade ≥3 adverse events (AEs), while one of the 16 treated with autogene cevumeran experienced grade 3 fever and hypertension. Every patient who received autogene cevumeran had grade 1/2 AEs.

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