Pancreatic cancer has proven resistant to immunotherapy in the past, but personalized mRNA vaccines may overcome that problem, according to a presentation at SSO 2023 – International Conference on Surgical Cancer Care.1
Results from a phase 1 trial showed that a personalized mRNA neoantigen vaccine can stimulate an immune response in patients with pancreatic ductal adenocarcinoma (PDAC).
The vaccine, autogene cevumeran, was given after surgery and in combination with atezolizumab and modified FOLFIRINOX (folinic acid, fluorouracil, irinotecan hydrochloride, and oxaliplatin).
The vaccine was “highly immunogenic” in half of patients and may have delayed recurrence, said study presenter Vinod P. Balachandran, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.
Rationale for an mRNA Vaccine for Pancreatic Cancer
“In terms of immunotherapies, I believe we are just at the beginning of identifying novel ways to harness the immune system to fight cancer,” Dr Balachandran said. “Certainly, the first method of doing so are the class of immune checkpoint inhibitors, which broadly seem to boost pre-existing antitumor immune responses.”
Dr Balachandran noted, however, that immune checkpoint inhibitors don’t appear to work in about 80% of cancers. Still, the immune system recognizes these cancers, and vaccines may be able to target the specific proteins the immune system recognizes.
Dr Balachandran said the cause of resistance to immunotherapy in pancreatic cancer has been attributed to a low mutation burden and few mutation-derived neoantigens.2 However, research suggests that long-term survivors of pancreatic cancer do harbor mutation-derived neoantigens suitable for vaccines.
In prior work, Dr Balachandran and colleagues found that the tumor tissue of long-term pancreatic cancer survivors had a 12-fold higher density of activated CD8+ T cells, compared with tissue from short-term survivors (P <.0001).3 In the long-term survivors, strong neoantigens had developed spontaneously, triggering the proliferation of neoantigen-specific T cells in their tumors.
Dr Balachandran’s research team wondered whether individualized mRNA neoantigen vaccines could spark the development of neoantigen-specific T cells as a component of potentially curative therapy for pancreatic cancer.
Trial of Autogene Cevumeran in PDAC
To test their hypothesis, Dr Balachandran and colleagues conducted a phase 1 trial in 20 patients with PDAC who had their tumors removed at potentially curative surgery (ClinicalTrials.gov Identifier: NCT04161755).1,4 Patients who had borderline-resectable tumors, had locally advanced or metastatic cancer, or had received neoadjuvant treatment were excluded from the trial.
The researchers sent patient tissue to colleagues in Mainz, Germany, who sequenced tumor DNA, normal DNA, and tumor RNA, computationally predicting and ranking neoantigens for custom manufacturing of vaccines. The resultant mRNA vaccine, autogene cevumeran, had up to 20 major histocompatibility complex (MHC)-1 and MHC-II restricted neoantigens.
To stimulate the immune system, patients were given a single dose of atezolizumab 6 weeks after surgery. Three weeks later, patients began 8 weekly intravenous priming doses of autogene cevumeran.
Vaccine priming was followed by treatment with modified FOLFIRINOX, started at week 21 and given every other week for 12 weeks. Three weeks after chemotherapy was complete, patients received a booster dose of autogene cevumeran.
Dr Balachandran reported results for 19 patients who received atezolizumab, of whom 16 were vaccinated.1 The reasons for failure to receive vaccine were inability to produce vaccine (n=1), initiation of treatment for a separate cancer (n=1), and disease progression prior to vaccination (n=1).
Vaccinations were delivered within 3 days of the intended benchmark times, suggesting the technology could be feasible in clinical practice.
The primary endpoint of the trial was safety. The regimen’s toxicity was considered modest. A single patient had grade 3 fever and hypertension, which was well below the study-defined safety threshold.
Immune responses were observed in 8 of 16 vaccinated patients (50%). In patients with an immune response, the T-cell clonal population expanded to as high as 10% of all peripheral blood T cells. This percentage was as high as 2.5% 2 years later.
At a median follow-up of 18 months, the median recurrence-free survival was not reached in responders and was 13.4 months in non-responders (hazard ratio, 0.08; 95% CI, 0.01-0.4, P =.003).
Based on these results, Dr Balachandran concluded that autogene cevumeran is safe and can be fully integrated into a routine clinical workflow.
“We believe it is highly immunogenic in 50% of unselected PDAC patients,” Dr Balachandran said. “This immunity preliminarily correlated with delayed PDAC recurrence, and we think this is a sufficient rationale now for future broader testing in PDAC patients. A follow-up randomized clinical trial is imminent.”
Disclosures: This research was partly supported by Genentech.
1. Balachandran VP. The next generation of vaccination approaches to the treatment of cancer: mRNA and designer cancer vaccines. Presented at SSO 2023 – International Conference on Surgical Cancer Care. March 22-25, 2023.
2. Łuksza M, Sethna ZM, Rojas LA, et al. Neoantigen quality predicts immunoediting in survivors of pancreatic cancer. Nature. 2022;606(7913):389-395. doi:10.1038/s41586-022-04735-9
3. Balachandran VP, Łuksza M, Zhao JN, et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature. 2017;551(7681):512-516. doi:10.1038/nature24462
4. Balachadran VP, Rojas LA, Sethna Z, et al. Phase I trial of adjuvant autogene cevumeran, an individualized mRNA neoantigen vaccine, for pancreatic ductal adenocarcinoma. Presented at ASCO 2022. June 3-7, 2022. Abstract 2516.