Abstract 5841: SARS-CoV-2 mRNA vaccines sensitize tumors to immune checkpoint blockade

Abstract Background: We previously reported that personalized mRNA vaccines enhance responses to immune checkpoint inhibition (ICI) in part by stimulating IFN-⍺ production. We hypothesized that mRNA vaccines encoding non-tumor antigens, including those targeting SARS-COV-2, would similarly augment responses to ICI. Methods: We utilized institutional databases to extract clinical data for patients with Stage III/IV non-small cell lung cancer (NSCLC) (n=2406) and metastatic melanoma (n=757) with biopsy specimens between August 2019 and August 2023, as well as a separate “tissue agnostic” cohort with pathology reports quantifying “PD-L1” from August 2020 to November 2023 (n=5, 524). We then generated a preclinical model of ICI-resistance with subcutaneous murine B16F0, and analyzed plasma from a cohort of healthy volunteers (n=5) at baseline and 6 hours, 24 hours, 1 week, and 2 weeks after SARS-COV-2 mRNA vaccination with NULISA-Seq and flow cytometry. Differences were assessed with Wilcoxon rank-sum tests, Cox proportional hazards regression, and Gehan-Breslow-Wilcoxon tests. Results: Median overall survival (OS) was doubled for patients with Stage IV NSCLC who received a SARS-COV-2 mRNA vaccine within 100 days of initiation of ICI compared to patients diagnosed before the pandemic (555 days vs 1120 days, HR 0.5, 95% CI 0.4-0.7) and contemporary patients who did not receive a vaccine (646 days vs 1120 days, HR 0.6, 95% CI 0.4-0.9, p=0.007). OS was unchanged for vaccinated patients who did not receive ICI and those who received non-mRNA vaccines. In the melanoma cohort, SARS-COV-2 mRNA vaccination was associated with substantially improved OS (HR 0.42, 95% CI 0.24-0.74, p=0.003) and progression free survival (HR 0.64, 95% CI 0.44-0.92, p=0.022). In our preclinical model, SARS-COV-2 mRNA vaccines stimulated a surge in many inflammatory cytokines including IFN-⍺, leading to systemic innate immune activation, expansion, activation, and persistence of tumor-reactive T cells, and increased expression of PD-L1 on tumor cells. SARS-COV-2 mRNA vaccines significantly inhibited growth of B16F0 tumors only when combined with ICI. This effect required Type I IFN signaling but was not recapitulated with systemic IFN-⍺ alone. We then recapitulated these results in human subjects, where SARS-COV-2 mRNA vaccinaties were associated with an 8-fold increase in IL-6 and at least 265-fold increase in IFN-⍺ (p<0.001) in five healthy volunteers. Finally, SARS-COV-2 mRNA vaccination within 100 days of biopsy was associated with a 23% increase in mean tumor proportion score (TPS) of PD-L1 in patients with NSCLC (31% vs 26%, p=0.029) and a 55% increase in mean TPS (14% vs 8.9%, p=0.029) in the tissue agnostic cohort. Conclusions: SARS-COV-2 mRNA vaccines are associated with a cytokine cascade that likely induces PD-L1 expression in tumors and augments responses to ICIs, leading to improved survival in patients with metastatic melanoma and NSCLC. Citation Format: Adam Grippin, Christiano Marconi, Sage Copling, Priti Gupta, Elliana Young, Padmanee Sharma, Don Gibbons, Hai Tran, Yon Son Betty Kim, Jianjun Zhang, Jennifer Wargo, John V. Heymach, Hector Mendez-Gomez, Wen Jiang, Elias Sayour, Steven H. Lin. SARS-CoV-2 mRNA vaccines sensitize tumors to immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5841.