Pancreatic ductal adenocarcinoma (PDAC) remains a highly aggressive and deadly disease with a poor prognosis. Devastating characteristics, including limited strategies for early detection and a fast growth rate, continue to make PDAC a significant clinical challenge. The latest estimates suggest that 88% of PDAC cases result in cancer mortality. In addition, globally rising incidence rates highlight the importance of researching new treatments to combat this particularly complex malignancy.
PDAC contains neoantigens, proteins that appear on the surface of cancer cells due to DNA mutations. Neoantigens trigger the immune response and help direct immune mechanisms against cancer cells harboring these markers. Thus, PDAC neoantigens have an excellent potential for vaccine development.
A recently conducted phase I trial evaluated a vaccine's ability to harness the potential of PDAC neoantigens. The researchers performing this study published their results in the Journal Nature.
Patients enrolled in the study underwent surgery to remove PDAC tumors. Researchers used the resected PDAC tumors to generate a personalized neoadjuvant vaccine (autogene cevumeran) for each patient. The researchers designed each personalized vaccine to target at least 20 neoantigens. After surgery, patients received additional treatment consisting of atezolizumab, an immune checkpoint inhibitor that targets the programmed death 1 ligand (PD-L1) in an effort to boost anti-tumor immunity, combination chemotherapy, comprised of folinic acid, fluorouracil, irinotecan, and oxaliplatin (mFOLFIRINOX), and autogene cevumeran.
Fifteen patients completed the full therapeutic regimen (atezolizumab, autogene cevumeran, and mFOLFIRINOX), and an additional patient received atezolizumab and autogene cevumeran without mFOLFIRINOX. The researchers found autogene cevumeran well tolerated by the patients and detected neoantigen-specific immune cells in half of the patients.
The researchers also evaluated the T cells, the immune cells responsible for killing cancer cells, in the blood by detecting how many cells resulted from expansion induced by the vaccine. The analysis showed that up to 10% of the total T cells in the blood were vaccine-expanded T cells. Notably, a vaccine booster could induce additional expansion, resulting in long-lasting, durable neoantigen-specific T cells.
Outcomes 18 months after treatment were compared between patients who generated vaccine-expanded T cells (responders) and those without vaccine-expanded T cells (non-responders). Responders had a longer median recurrence-free survival, as at 18 months, more than half of the responders had not experienced a recurrence, and the non-responders experienced recurrence at an average of 13.4 months.
The authors conclude that combination therapy consisting of surgery followed by adjuvant atezolizumab, autogene cevumeran, and mFOLFIRINOX promotes T cell activity and may delay PDAC recurrence. Additional studies to evaluate the treatment regimen's efficacy are needed to validate its efficacy.
Sources: Rad Oncol, Diagnostics, CA, Nature (Balachandran), Nature (Rojas)
