Mutant KRAS vaccine with dual checkpoint blockade in resected pancreatic cancer: a phase I trial

Area of Science:

• Oncology
• Immunology
• Vaccine Development

Background:

• Pancreatic adenocarcinoma is a deadly cancer with limited treatment options.
• KRAS mutations are common drivers in pancreatic cancer.
• Targeting KRAS mutations with immunotherapy is a promising strategy.

Purpose of the Study:

• To evaluate the safety and immunogenicity of a novel pooled synthetic long peptide vaccine targeting six KRAS mutations.
• To assess the vaccine's effect in combination with ipilimumab and nivolumab in patients with resected pancreatic adenocarcinoma.
• To measure T cell responses to KRAS mutations and survival outcomes.

Main Methods:

• Phase I clinical trial.
• Administered a pooled synthetic long peptide vaccine targeting KRAS mutations (G12V, G12A, G12R, G12C, G12D, G13D) with ipilimumab and nivolumab.
• Monitored safety, T cell responses (IFNγ-producing), disease-free survival, and overall survival.

Main Results:

• Vaccine-related adverse events were predominantly grade 1-2, indicating good safety.
• 11/12 patients showed a significant increase in T cell response to KRAS antigens.
• 10/12 patients demonstrated a tumor-specific T cell response.
• Generated cross-reactive T cells recognizing multiple KRAS mutations.

Conclusions:

• The KRAS peptide vaccine is safe and well-tolerated in patients with resected pancreatic adenocarcinoma.
• The vaccine elicits robust and diverse anti-tumor T cell immunity.
• These findings support further investigation of mutant KRAS vaccines in pancreatic cancer treatment.