Background
As a cancer type that is often discovered in advanced stages, pancreatic cancer has a high mortality rate due to its vital "stealth" and "metastatic" nature, earning its reputation as the "king of cancers." Taking pancreatic ductal adenocarcinoma (PDAC) as an example, only 88% of patients can survive for five years after diagnosis. Apart from being often diagnosed at later stages, another reason for the high mortality rate of pancreatic cancer is its insensitivity to conventional cancer treatments, including Nobel Prize-winning immunotherapy checkpoint inhibitors.
PDAC has a meager response rate, less than 5%, to the highly popular immunotherapy checkpoint inhibitor treatment. This is because, compared to other immunotherapy-sensitive cancers, PDAC has a lower mutation rate, resulting in a weaker generation of neoantigens and subsequently induced cell immune intensity. Even if T cells are reactivated through immunotherapy checkpoint inhibitors, they cannot effectively kill cancer cells.
However, researchers have discovered its vulnerability in some patients with more prolonged survival. Once sufficient neoantigen-specific T cells are present, our immune system can effectively kill cancerous cells and prolong the patient's survival.
Experiment and Result
Personalized mRNA Vaccines
Individual variation exists in the types of neoantigens present in different PDAC patients. Researchers have employed a personalized approach to generate mRNA vaccines tailored to each individual. The research team first performed sequencing on surgically resected PDAC tumors and normal tissues and, based on the sequencing mutation results, designed mRNA vaccines containing corresponding neoantigen sequences.
Out of the 34 patients participating in the clinical trial, 16 received the personalized mRNA vaccine after surgery, along with the administration of atezolizumab (PD-L1 antibody) and mFOLFIRINOX adjuvant chemotherapy (14 patients).
Regarding safety, among the patients who received the mRNA vaccine injection, one experienced a grade 3 adverse event manifested as fever and hypertension. All 16 participants experienced grade 1 to 2 side effects. Researchers considered these side effects acceptable for PDAC patients, indicating that post-surgical administration of mRNA vaccines in PDAC patients is relatively safe.
Apart from safety, the most exciting finding is that T-cell responses were detected in half of the patients who received the mRNA vaccine injection. Among the 230 neoantigens introduced by the vaccine, T-cell responses were seen for 25 of them in in vitro experiments. Furthermore, half of the T cell responses could recognize more than one neoantigen. Despite individual differences, researchers unsurprisingly detected neoantigen-specific immune responses in the peripheral blood of these patients.
These data collectively demonstrate that mRNA vaccines can elicit T-cell solid responses in PDAC patients.
Persistence and Effectiveness
After observing T cell responses in vitro, researchers further investigated whether these T cells could exert anti-cancer effects and if the responses were long-lasting. They used a technology called CloneTrack to detect vaccine-induced T-cell clone expansion in eight responders. The mRNA vaccine increased the proportion of these specific clones from undetectable levels to a maximum of 10%. 75% of patients had neoantigen-specific clones among these T cell clones. Of the 41 expanded T cell clones, 21 exhibited neoantigen specificity.
These data demonstrate that mRNA vaccines can induce the expansion of specific multi-clonal T cells.
Further single-cell RNA sequencing results revealed that these T cell clones were predominantly CD8+ T cells expressing soluble markers and gamma interferon, similar to the phenotype of T cells stimulated by mRNA viral vaccines. Peripheral blood cell experiments also showed that these cells were primarily CD8+ T cells.
Researchers also observed persistent T-cell responses in patients receiving concurrent chemotherapy, indicating that chemotherapy did not influence the vaccine's efficacy. Within two years after surgery, booster injections could re-ignite T cell expansion, and the T cell clones stimulated by booster injections maintained good consistency with the previously generated T cell clones.
These data demonstrate that mRNA vaccines stimulate CD8+ T cell responses that are both effective and long-lasting.
Clinical Breakthroughs
Although extensive cellular experiments and in vitro data have demonstrated that mRNA vaccines can induce neoantigen-specific immune responses, the actual effectiveness needs to be observed in clinical settings. In a follow-up study with a median duration of 18 months, all eight responders remained alive without recurrence. In contrast, all eight non-responders experienced recurrence, with a median recurrence time of 13.4 months. Responders also had lower levels of the PDAC marker CA19-9 compared to non-responders. To demonstrate that this remarkable effect is not due to patient selection, health status differences, or variations in T cell proportions, researchers investigated humoral and cellular immunity, immune cell ratios, and genetic characteristics in both groups and found comparable results.
Finally, in patient number 29, who potentially had liver metastasis, researchers also discovered the potential of vaccine-induced T cells in clearing small metastatic lesions. As a responder, patient 29 experienced liver damage and increased tumor marker levels after vaccination. However, biopsy samples did not reveal tumor cells but showed the presence of numerous lymphocytes, including 15 T cell clones induced by the mRNA vaccine. This suggests that mRNA vaccines may help the immune system clear metastatic lesions.
These clinical data provide solid evidence for the outstanding performance of mRNA vaccines in PDAC treatment.
Conclusion
In conclusion, the study on personalized mRNA vaccines for PDAC has shown promising results. The vaccines are safe, stimulate T-cell responses, and exhibit persistence and effectiveness. Clinical outcomes demonstrate improved survival and reduced recurrence. Additionally, the vaccines show the potential to clear metastatic lesions. These findings provide strong evidence for the outstanding performance of mRNA vaccines in PDAC treatment.
This study conducted extensive cellular experiments to investigate the specificity of T-cell clones for neoantigen peptides. GenScript is also honored to be involved and provide neoantigen peptide synthesis service in this research.
Reference
[1] Rojas, L.A., Sethna, Z., Soares, K.C. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature (2023). https://doi.org/10.1038/s41586-023-06063-y
