Mutant KRAS peptide vaccine with dual checkpoint blockade in metastatic colorectal cancer: a phase I trial

Area of Science:

• Oncology
• Immunotherapy
• Cancer Vaccines

Background:

• Immune checkpoint inhibitors (ICIs) demonstrate limited efficacy in mismatch repair proficient/microsatellite stable (MMRp/MSS) colorectal cancer (CRC).
• Mutations in KRAS (KRASm), common in MMRp/MSS CRC, can serve as neoantigens for targeted therapies.
• Therapeutic vaccines targeting KRAS mutations present a potential strategy to enhance anti-tumor immunity.

Purpose of the Study:

• To evaluate the safety and immunogenicity of a novel mutant KRAS (mKRAS) peptide vaccine (mKRAS-VAX) in combination with nivolumab and ipilimumab.
• To assess the preliminary efficacy of this combination therapy in patients with pretreated metastatic MMRp/MSS CRC.

Main Methods:

• A single-arm, phase I clinical trial (NCT04117087) involving 13 patients with pretreated metastatic MMRp/MSS CRC.
• Patients received mKRAS-VAX, a pooled peptide vaccine targeting six common KRAS mutations, along with nivolumab and ipilimumab.
• Safety was assessed by adverse events, and immunogenicity was measured by ex vivo IFNγ ELISpot assays detecting mKRAS-reactive T-cells.

Main Results:

• The combination therapy met primary endpoints for safety and immunogenicity within 17 weeks post-vaccination.
• All adverse events related to mKRAS-VAX were low-grade (1 or 2) and did not increase severe immune-related adverse events.
• Tumor-specific mKRAS-reactive T-cells increased in 75% of evaluable patients (8/12) via ELISpot and 100% (12/12) after in vitro expansion.

Conclusions:

• The mKRAS peptide vaccine combined with dual immune checkpoint inhibitors is safe and immunogenic in patients with advanced MMRp/MSS CRC.
• This therapeutic approach shows potential for generating anti-tumor immune responses in a patient population with limited treatment options.
• Further clinical development of mKRAS vaccines in combination with ICIs is supported for advanced MMRp/MSS CRC.