Abstract Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but do not produce durable responses in most patients. Personalized cancer vaccines have been proposed as tools to sensitize tumors to ICIs, but are limited by cost and manufacturing time. We investigated whether mRNA vaccines targeting non-tumor antigens could also sensitize tumors to ICIs. Methods: We retrospectively evaluated overall survival among patients treated with ICIs at MD Anderson, separating patients into groups based on the timing of their most recent SARS-CoV-2 mRNA vaccination prior to ICI initiation. We utilized murine tumor models (B16F0 melanoma, LLC lung carcinoma) to interrogate mechanisms of response and correlates of synergy with ICIs. We then validated these immunologic correlates in patients and healthy volunteers. Results: Patients who received SARS-CoV-2 mRNA vaccines within 100 days of initiating first-line ICI had improved OS relative to those who did not (HR 0. 70, 95% CI 0. 65-0. 75). This effect was time-dependent, as patients who received a vaccine within 30 days of initiating first-line ICI experienced further improved survival relative to those who received a vaccination within 30-100 days of initiating ICI (HR 0. 62, 95% CI 0. 51-0. 76). No survival advantage was identified among patients who received vaccines targeting influenza (HR 1. 00, 95% CI 0. 90-1. 10) or pneumonia (HR 0. 94, 95% CI 0. 77-1. 13) without COVID mRNA vaccination. Preclinical RNA-LNP formulations encoding SARS-CoV-2 spike protein validated clinical observations, significantly suppressing growth of established B16F0 and LLC when combined with ICI. Mechanistically, RNA-LNPs drove a cytokine cascade including IFN⍺, IL-6, and CXCL-10, leading to rapid myeloid and dendritic cell activation, antigen presentation, and priming of tumor-reactive, tumor-infiltrating CD8+ PD1+ effector/memory T cells. Although tumor cells upregulated PD-L1 expression following vaccination, concomitant PD-1/PD-L1 blockade overcame this resistance mechanism, sustaining cytotoxic T-cell activity and driving tumor regression. Similar correlates of response were seen in humans, including cytokine production and innate immune activation in healthy volunteers, and increased PD-L1 on tumor cells in cancer patients (N=5, 524). Conclusions: Taken together, these results suggest that mRNA vaccines targeting infectious disease antigens may sensitize tumors to ICIs. Citation Format: Adam Grippin, Sage Copling, Christiano Marconi, Chen Braun, Cole Woody, John Heymach, Jennifer Wargo, Pamela Sharma, Wen Jiang, Elias Sayour, Steven Lin. Mechanisms by which mRNA vaccines augment responses to immune checkpoint blockade abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr NG05.
Grippin et al. (Fri,) studied this question.