Immune Response to Investigational RNA Vaccine for Pancreatic Cancer Continues to Correlate with Clinical Benefit

Results are from a median follow-up of three years

SAN DIEGO – An adjuvant treatment regimen that included autogene cevumeran, an investigational individualized neoantigen-specific mRNA vaccine, induced durable and functional T-cell responses that were associated with a reduced risk of disease recurrence in certain patients with resectable pancreatic cancer, according to three-year follow-up results reported at the American Association for Cancer Research (AACR) Annual Meeting 2024, held April 5-10.

Pancreatic cancer is a highly fatal disease, and even with surgery, only about 13% of patients are alive five years after diagnosis, explained Vinod Balachandran, MD, a surgical oncologist and member of the David M. Rubenstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center. “Chemotherapy, radiation, targeted therapy, and current immunotherapies are also largely ineffective in pancreatic cancer, so new therapies are urgently needed for patients who face this deadly disease.”

Since cancer arises from the patient’s own cells, it can be hard for the immune system to distinguish cancer cells as foreign and mount a response against them, Balachandran explained. Cancer vaccines aim to activate an antitumor immune response by training the patient’s immune cells to recognize cancer cells.

Researchers have found that individual tumor mutations can give rise to neoantigens, proteins that are exclusively present in cancer cells and can trigger an immune response, making them ideal targets for immunotherapy. “Neoantigen-specific cancer vaccines must be custom-made for every patient, so we needed a technology that would allow rapid manufacture and delivery, together with robust immune activation,” Balachandran noted.

To address these requirements, Balachandran and colleagues explored the use of an mRNA-based cancer vaccine, autogene cevumeran, to target up to 20 unique neoantigens identified from each patient’s tumor. Balachandran explained that an mRNA platform may allow vaccines to be manufactured relatively quickly and delivered to the patient without a significant delay in their care.

Balachandran and colleagues conducted an investigator-initiated, single-center phase I clinical trial to evaluate the safety and immunogenicity of adjuvant autogene cevumeran in combination with atezolizumab (Tecentriq) and modified FOLFIRINOX chemotherapy for patients with resectable pancreatic cancer. Previously reported trial results showed that the treatment was tolerable, feasible, and induced immune responses (as measured by high-magnitude neoantigen-specific T-cell expansion) in eight of 16 evaluable patients. Further, at a median follow-up of 1.5 years, the eight patients who had vaccine-induced T-cell responses had a significantly longer median recurrence-free survival (not reached) than the eight patients who did not (13.4 months).

At this year’s AACR Annual Meeting, the researchers reported results from an extended follow-up. After a median follow-up of three years, the eight patients with vaccine-induced T-cell responses continued to have significantly longer median recurrence-free survival (not reached) compared with those who did not experience an immune response (13.4 months).

Furthermore, autogene cevumeran led to the expansion of multiple CD8+ T cell clones in the eight responding patients—98% of which were not present in blood, tumors, or adjacent tissue prior to vaccination. Over 80% of the expanded CD8+ T cell clones persisted in the blood long-term at substantial fractions (median 0.1% of all blood T cells). CD8+ T cells isolated up to 3 years post-vaccination remained responsive to target neoantigens in ex vivo rechallenge experiments in six of eight patients.

“Our data indicate that autogene cevumeran can induce CD8+ T cells with significant longevity, substantial magnitude, and durable function,” summarized Balachandran. “The findings that individualized neoantigen-specific cancer vaccines can induce a robust immune response that correlates with delayed disease recurrence continues to support these vaccines as an encouraging therapeutic approach for pancreatic cancer.”

He added that an ongoing randomized phase II clinical trial will compare the efficacy and safety of autogene cevumeran in combination with atezolizumab and FOLFIRINOX with standard-of-care FOLFIRINOX in patients with resectable pancreatic cancer.

A limitation of the study was the small sample size and its single-arm design.

The clinical trial was sponsored by Memorial Sloan Kettering Cancer Center. The clinical trial and biomarker studies were funded by Genentech and BioNTech (the developers of autogene cevumeran), as well as by the imCORE, Stand Up To Cancer, the Lustgarten Foundation, and the National Cancer Institute Pancreatic Cancer Microenvironment Network. Balachandran reports honoraria and research support from Genentech; research support from Bristol Myers Squibb; and patent applications for related work on antigen cross-reactivity, tracking vaccine-expanded T-cell clones, and neoantigen quality modeling.

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