Using mRNA tailored to each patient’s tumour, a novel vaccine may have staved off the return of one of the deadliest forms of cancer in half of those who received it, according to results reported by a group of scientists a week ago.
Five years ago, the small group of cancer scientists in Maine, Germany, drew up an audacious plan: they would test their novel cancer vaccine against one of the most virulent forms of the disease, a cancer notorious for roaring back even in patients whose tumours had been removed.
The vaccine might not stop those relapses, they figured. But patients were desperate. And the speed with which the disease, pancreatic cancer, often recurred, could work to the scientists’ advantage: for better or worse, they would quickly find out whether the vaccine helped.
Recently, reports The New York Times, the scientists reported results that defied the long odds. The vaccine provoked an immune response in half of the patients treated, who showed no relapse of their cancer during the course of the study, and a finding outside experts described as extremely promising.
The study was published in Nature, and marks a landmark in the long movement to make cancer vaccines tailored to individual patients’ tumours.
Researchers at Memorial Sloan Kettering Cancer Centre in New York, led by Dr Vinod Balachandran, extracted patients’ tumours and shipped samples to Germany. There, scientists at BioNTech analysed the genetic makeup of certain proteins on the surface of the cancer cells.
They then produced personalised vaccines designed to teach each patient’s immune system to attack the tumours. Like BioNTech’s Covid shots, the cancer vaccines relied on messenger RNA. In this case, the vaccines instructed patients’ cells to make some of the same proteins found on their excised tumours, potentially provoking an immune response that would come in handy against actual cancer cells.
“This is the first demonstrable success, despite the preliminary nature of the study, of an mRNA vaccine in pancreatic cancer,” said Dr Anirban Maitra, a specialist in the disease at the University of Texas MD Anderson Cancer Centre, who was not involved in the study. “By that standard, it’s a milestone.”
The study was small: only 16 patients, all of them white, were given the vaccine, part of a treatment regimen that also included chemotherapy and a drug intended to keep tumours from evading their immune responses.
And the study could not entirely rule out factors other than the vaccine having contributed to better outcomes in some patients.
But that scientists could create, quality-check and deliver personalised cancer vaccines so quickly – patients began receiving the vaccines intravenously roughly nine weeks after having their tumours removed – was a promising sign, experts said.
Since the beginning of the study, in December 2019, BioNTech has shortened the process to under six weeks, said Dr Ugur Sahin, a co-founder of the company, who worked on the study. Eventually, the company intends to make cancer vaccines in four weeks.
And since it first began testing the vaccines about a decade ago, BioNTech has lowered the cost from roughly $350 000 per dose to less than $100 000 by automating parts of production.
A personalised mRNA cancer vaccine developed by Moderna and Merck reduced the risk of relapse in patients who had surgery for melanoma, a type of skin cancer, the companies announced last month. But the latest study set the bar higher by targeting pancreatic cancer, which is thought to have fewer of the genetic changes that would make it ripe for vaccine treatments.
In patients who did not appear to respond to the vaccine, the cancer tended to return around 13 months after surgery. Patients who did respond, though, showed no signs of relapse during the roughly 18 months they were tracked.
Intriguingly, one patient showed evidence of a vaccine-activated immune response in the liver after an unusual growth developed there. The growth later disappeared in imaging tests.
“It’s anecdotal, but it’s nice confirmatory data that the vaccine can get into these other tumour regions,” said Dr Nina Bhardwaj, who studies cancer vaccines at the Icahn School of Medicine at Mount Sinai.
Scientists have struggled for decades to create cancer vaccines, in part because they trained the immune system on proteins found on tumors and normal cells alike.
Tailoring vaccines to mutated proteins found only on cancer cells, though, potentially helped provoke stronger immune responses and opened new avenues for treating any cancer patient, said Ira Mellman, vice-president of cancer immunology at Genentech, which developed the pancreatic cancer vaccine with BioNTech.
“Just establishing the proof of concept that vaccines in cancer can actually do something after, I don’t know, thirty years of failure is probably not a bad thing,” Mellman said. “We’ll start with that.”
Study details
Personalised RNA neoantigen vaccines stimulate T cells in pancreatic cancer
Luis Rojas, Zachary Sethna, Vinod Balachandran, et al.
Published in Nature on 10 May 2023
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA–lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.
See more from MedicalBrief archives:
mRNA vaccine can recognise neoantigens in pancreatic cancers – US study
PARP inhibitor shrinks tumours in pancreatic cancer with mutations
Cancer: Survivability is changing fast
World Cancer Day: A cure is 5-10 years away – WHO expert