In a recently published article in natureresearchers conducted a phase I clinical trial of a personalized messenger nucleic acid (mRNA) antigen vaccine based on uridine mRNA-lipoplex nanoparticles.
The study was conducted among 28 patients with pancreatic ductal adenocarcinomas (PDACs) who received surgical treatment at Memorial Sloan-Kettering Cancer Center (MSK) in New York City, United States (US), between December 2019 and August 2021.
Stady: Novel antigen-specific RNA vaccines stimulate T cells in pancreatic cancer. Image credit: mi_viri / Shutterstock.com
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths worldwide. With an ever-increasing incidence, a response rate of less than five percent to immune checkpoint inhibitors, and a survival rate of 12 percent over the past 60 years, PDAC will claim many more lives by 2025.
Another worrying aspect of PDAC is that approximately 90% of patients experience disease recurrence within seven to nine months of surgical resection, its only treatment, and the five-year overall survival (OS) is 10% or less. In such cases, targeted radiation therapies also fail.
Previous studies predicted that most PDACs harbor fewer neoantigens, in part due to their low mutation rate. These mutated proteins identify cancers as foreign, which facilitates infiltration T cells in PDACs.
Thus, there is a need for novel strategies that can effectively introduce multiple new antigens to induce novel antigen-specific T cells and improve patient outcomes, for example, eliminating micrometastases and delaying recurrence.
In this regard, personalized vaccines based on mRNA technology can be very beneficial. They have effectively introduced many novel antigens into clinical stage formulations and have been easily integrated into routine oncology workflows.
In this study, the researchers administered atezolizumab, autogene cevumeran, and mFOLFIRINOX sequentially in 28 patients who had undergone surgery to determine how each immunotherapy modified antigen-specific T-cell cells for novel antigens.
The researchers set standard times for starting these three treatments after surgery. They administered a single 1200 mg intravenous dose of atzolizumab in the sixth week.
For eligible patients, they administered nine doses of 25 mcg intravenously of autologous cevumeran between weeks 9 and 46. Of these, the first seven doses were weekly introductory doses, and the ninth was a booster dose. Finally, they administered 12 cycles of mFOLFIRINOX by the start of week 21.
The primary and secondary endpoints were safety, 18-month recurrence-free survival (RFS) and 18-month OS, respectively. Analyzed the first panel in a cohort evaluable for safety and an RFS-related immune response in a cohort evaluable for biomarkers.
Furthermore, the team used an ex vivo ELISpot assay for interferon gamma (IFNγ) to measure endogenous cevumeran-induced high volume T-cell responses without identifying CD8+ from CD4+ responses.
In addition, they used CloneTrack, a novel mathematical immunoassay method based on the T-cell receptor (TCR) Vβ sequence, to investigate the diversity and specificity of expanded T-cell clones with an autologous gene – sevomeran.
Finally, the researchers used single-cell RNA sequencing to study the phenotype and functions of T cells induced by autologous cerumen therapy.
Of all 19 patients treated with atezolizumab, 16 patients subsequently received cevumeran, and 15 also received mFOLFIRINOX. The authors provide preliminary evidence that the adjuvant autologous cefomeran, a novel personalized antigen vaccine used in combination with the adjuvant atizolizumab and mFOLFIRINOX, has a favorable safety profile.
In addition, it induced significant neoantigen-specific T cell activity in 50% of patients with surgically resected PDAC implicated in late recurrence.
Moreover, these neoantigen-specific T cells were durable and persisted for up to 2 years despite mFOLFIRINOX treatment. Even known prognostic variables, such as positive margin disease, did not confound vaccine response with late tumor recurrence.
Induction of high volume T-cell responses highlighted the need for biomarkers to help identify patients and tumors optimal for this immunotherapy.
As high volume T-cell responses have contributed to a favorable clinical outcome, many investigators are pursuing strategies to ensure further refinement of high volume T cell responses.
For example, they are trying to improve the effectiveness of the mRNA vaccine and expand the discovery space for novel antigens to include single nucleotide variations (SNVs).
Furthermore, in this trial, responders and non-responders had similar numbers of vaccine-new antigens drawn from a similar number of tumor mutants. However, the tumors in the responders were more reproducible than the tumors seen in long-term survivors of PDACs.
Based on this finding, the authors speculated that the immune system readily identifies a clonal prototumour to respond to the vaccine.
The link between the quality of novel antigens and the new antigens of an immunogenic vaccine has highlighted that those neoantigens are likely to possess higher immunogenic traits desirable for vaccines.
Thus, future studies should investigate whether tumor reproducibility and novel antigen quality could be biomarkers of personalized vaccine modalities response. Additionally, the authors suggested that these vaccines should be tested in patients with minimal residual disease because vaccine efficacy requires an optimally functioning immune system.
The present study demonstrated that, in a short period of nine weeks, it is possible to customize novel antigen mRNA vaccines for the PDAC patients evaluated in this study and fully integrate them into the clinical oncology workflow after complex oncological surgery.
Future studies should evaluate these vaccines at a faster time to adjuvant antiretrovirals and across a variety of PDAC patients.
Based on experience with mRNA-based SARS-CoV-2 vaccines, it appears that rapid availability of specific cancer and chemotherapy-specific vaccination is feasible, as well as a reduction in the time to manufacture of these vaccines.