Abstract B125: SARS-CoV-2 mRNA vaccines sensitize tumors to immune checkpoint blockade

Abstract Although immune checkpoint inhibitors (ICI) have substantially extended survival in a subset of patients with cancer, they remain ineffective in most patients. Personalized mRNA vaccines sensitize tumors to ICIs in part by unleashing a cytokine/chemokine cascade that broadly activates immune cells. Since this cascade is not dependent on mRNA species, we hypothesized that mRNA vaccines encoding non-tumor-specific antigens might also be used to reset immunotolerance and sensitize response to ICIs. Here, we show that mRNA vaccines targeting SARS-CoV-2 spike protein dramatically augment responses to ICIs. In two cohorts of patients with non-small cell lung cancer and metastatic melanoma, receipt of a COVID mRNA vaccine within 100 days of ICI initiation was associated with near doubling of overall survival after controlling for over 38 covariates with Cox Proportional Hazards Regression. Preclinical models confirmed that mRNA vaccines targeting SARS-COV-2 sensitize response to ICIs. By inducing a surge in interferon-α and Th1 chemokines, spike mRNA vaccines mediate antigen presenting cell co-localization with T cells in lymphoid organs for induction of anti-tumor immunity. Due to increases in PD-L1 on tumor cells, concomitant ICI treatment elicits increased PD-1+ T cells and epitope spreading against cancer associated antigens. Similar correlates of response were seen in both patients and healthy volunteers. Together, these results demonstrate that clinically available mRNA vaccines targeting non-tumor antigens are potent immune modulators capable of sensitizing tumors to ICIs. Citation Format: Adam Grippin, Christiano Marconi, Sage Copling, Hector Mendez-Gomez, Jennifer Wargo, John Heymach, Wen Jiang, Elias Sayour, Steven H Lin. SARS-CoV-2 mRNA vaccines sensitize tumors to immune checkpoint blockade [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B125.