Dissecting mechanisms by which mRNA vaccines encoding nontumor antigens initiate antitumor immunity

Immune checkpoint inhibitors (ICIs) have significantly improved survival in many cancer patients, but most still fail to respond to these treatments. We and others have demonstrated that personalized mRNA lipid nanoparticle vaccines enhance antitumor immunity in combination with PD-1 inhibition. However, we recently found that mRNA vaccines targeting non-tumor antigens can also act as potent adjuvants to immune checkpoint blockade, leading to improved survival in non-small cell lung cancer and metastatic melanoma patients. This proposal aims to interrogate the mechanisms by which mRNA vaccines targeting non-tumor antigens generate antitumor immunity. Our overarching hypothesis is that much of the benefit of personalized mRNA vaccines is derived from their ability to broaden the T cell repertoire by enhancing DC priming of T cells in tumors and tdLNs, leading to antitumor immunity that is most magnified by CTLA-4 blockade. We will test this hypothesis through three specific aims: Aim 1: Determine the mechanism by which non-neoantigen mRNA vaccines produce tumor-reactive T cells. Aim 2: Dissect the mechanism by which mRNA vaccines preferentially augment antitumor responses to CTLA-4 blockade. Aim 3: Interrogate the importance of antigen selection for mRNA cancer vaccines in combination with PD-1 and CTLA-4 blockade. This study is designed to offer a transformational shift in our understanding of mRNA vaccines, highlighting their potential not only as tumor-targeting agents but also as powerful adjuvants for immune checkpoint blockade. Ultimately, this research aims to leverage the innate adjuvanticity of mRNA to facilitate the development of universal cancer vaccines. Project Number: 1K08CA308866-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Adam Grippin | Institution: UNIVERSITY OF TX MD ANDERSON CAN CTR, HOUSTON, TX | Award Amount: $136,270 | Activity Code: K08 | Study Section: Special Emphasis Panel[ZRG1 CTH-K (83)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11282708