Combination therapy of KRAS G12V mRNA vaccine and pembrolizumab: clinical benefit in patients with advanced solid tumors

Abstract

mRNA-based therapeutics have gained the public’s attention in the post-COVID era. The application of mRNA vaccines is not limited to infectious diseases but extends to broader areas, such as cancers and rare genetic disorders. 1 , 2 , 3 This first-in-human study demonstrated the safety and preliminary efficacy of mRNA vaccines targeting multiple neoantigens in 13 patients with advanced melanoma. 4 The vaccines significantly reduced recurrent metastatic events, improving progression-free survival. Steven Rosenberg’s group later reported that mRNA vaccines could generate mutation-specific T-cell responses against predicted neoepitopes in 4 patients with metastatic gastrointestinal cancer. 5 However, no objective clinical responses were observed. Therefore, whether the application of mRNA vaccines can be expanded to cold tumors such as gastrointestinal tumors remains to be addressed. Recently, the efficacy of personalized mRNA vaccines targeting multiple neoantigens in combination with programmed death 1 ligand (PD-L1) inhibitors and mFOLFIRINOX (a modified version of a four-drug chemotherapy regimen) in delaying recurrence in pancreatic cancer patients after surgical resection was reported. 6 The median recurrence-free survival was not yet reached for vaccine responders (50% of the patients enrolled), compared with an average of 13.4 months for nonresponders. Similarly, personalized mRNA vaccines with up to 34 neoantigens plus the PD-1 inhibitor pembrolizumab slowed recurrence in postsurgical patients with melanoma in the phase IIb KEYNOTE-942 trial. 7 These early trials suggested that utilizing personalized vaccines to cover multiple neoantigens in the postsurgical setting with a low tumor load is a practical strategy for mRNA therapeutics. Whether a tumor vaccine can be used in late-stage cancer patients with a high tumor load is unknown.

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