Personalized Cancer Vaccine Leads to Delays in Pancreatic Cancer Recurrence

Adjuvant treatment with the personalized neoantigen vaccine based on uridine mRNA lipoplex nanoparticles, autogene cevumeran, led to delayed pancreatic cancer recurrence in patients with pancreatic ductal adenocarcinoma (PDAC) who responded to the vaccine, according to data from a phase 1 trial (NCT04161755) presented at the 2024 AACR Annual Meeting.¹ The personalized vaccine expanded CD8 T cells de novo—which may expand the vaccine-eligible cancer pool—and led to a substantial estimated longevity and durable function as well.

At a median follow-up of 3.2 years, the median recurrence-free survival (RFS) was not yet reached in patients with PDAC who responded to the vaccine (responders; n = 8) compared with 13.4 months in those who received the vaccine but did not generate vaccine-induced T cells (non-responders; n = 8; HR, 0.14, 0.03-0.59; P = .007).

Notably, in a previous presentation of data at a 1.5-year follow-up, non-responders experienced a median RFS of 13.4 months and in responders, the median RFS had not been reached (HR, 0.08, 0.01-0.4; P = .003). Findings from the 1.5-year follow-up led investigators to evaluate remaining questions, such as whether the vaccine-induced T cells can last long term, in the 3.2-year follow-up.

Furthermore, investigators reported that most vaccine-induced T cell clones persist for more than 2 years. Following the trace of these clones back to various sources including tumors, adjacent tissues, and draining lymphatic basins, investigators found that of the 79 vaccine-induced T cell clones identified, only 2.5% of these clones are pre-existing in host tissues. In contrast, 73.0% of PD-L1 expanded clones are found in host tissues.

“This particular vaccine expands CD8 T cells, we believe de novo, thus not restricting vaccine-induced immune response to patients who have pre-existing T cells, theoretically expanding the vaccine-eligible cancer pool beyond pancreatic cancer,” Vinod P. Balachandran, MD, stated in a presentation of the data. “These vaccine-induced T cells have a substantial estimated longevity and durable function, which are desirable features for cancer vaccines. At the 3-year follow-up time, we find that vaccine immunity continues to correlate with delayed pancreatic cancer recurrence.”

Furthermore, Balachandran, an associate attending surgeon at Memorial Sloan Kettering Cancer Center, went on to state, “we believe vaccines could be the next promising cancer immunotherapy because the fundamental challenge for cancer vaccines has been to generate strong, specific, functional, and durable T cells in disease hosts.”

Despite the promise of vaccines in the treatment landscape, Balachandran highlighted key areas of unmet need with the utility of these products: to identify optimal antigens that are both tumor-specific and immunogenic, as well as a modular delivery platform that can vaccinate against an evolving population of clones in hosts who have optimal fitness status and can thus sustain high magnitude tumor-specific T cells.

To address these unmet needs in care, investigators shifted their focus to PDAC, a cancer that has been historically considered unsuitable for vaccine treatment. However, by observing long-term PDAC survivors who developed natural T cell immunity to the disease, Balachandran said investigators reported that passenger mutation-derived neoantigens delivered via mRNA in minimal residual disease could serve as a potential therapeutic approach. In order validate this hypothesis, this investigator-initiated, single-center, phase 1 clinical trial was initiated.^1,2

The trial aimed to assess whether personalized RNA vaccines targeting mutation-derived neoantigens could expand neoantigen-specific T cells when administered as an adjuvant vaccine, as this approach may consequently delay the recurrence of PDAC following surgery. Eligible patients enrolled had surgically resectable PDAC that was not borderline resectable or advanced/metastatic, and patients who had been previously treated with neoadjuvant therapy were not eligible. The study’s primary end point was safety and additional end points of immunogenicity, feasibility, and 18-month RFS were also evaluated.

Following removal of the primary PDACs, individualized RNA neoantigen vaccines were synthesized for each patient. After surgery, patients received treatment with one dose of the immune checkpoint inhibitor atezolizumab (Tecentriq), a PD-L1 blocking antibody. Then, patients were treated with 8 consecutive doses of their personalized vaccine, followed by standard of care modified FOLFIRINOX and a vaccine booster, dose 9. Investigators found that treatment stimulated high levels of vaccine-induced T cells in 50% of patients with pancreatic cancer regardless of selection criteria.

This investigator-initiated study also revealed that vaccine-induced T cells, following the initial 8 priming doses, exhibit a median lifespan of approximately 1 year. However, this median lifespan extends to 6 years after a single vaccine booster, even with patients undergoing chemotherapy in the interim between priming and boosting. Findings further demonstrated that over 80% of these vaccine-induced T cell clones can stay in patients for more than 2 years post-treatment.

Balachandran also stated that this study has since moved on to a randomized phase 2 clinical trial that is currently open for enrollment.

References

1. Sethna Z, Guasp P, Reiche C, et al. Personalized RNA neoantigen vaccines induce long-lived CD8+ T effector cells in pancreatic cancer. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA.
2. Rojas LA, Sethna Z, Soares KC, et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature. 2023;618(7963):144-150. doi:10.1038/s41586-023-06063-y