Work

IMMU-89. Association of SARS-COV-2 mRNA vaccines on PD-L1 expression and clinical tresponses to immune checkpoint blockade in patients with intracranial tumors

Year: 2025

Type: article

Abstract: We previously demonstrated that personalized mRNA vaccines enhance responses to immune checkpoint inhibitors (ICI) in part by stimulating production of Type I IFN. Since this surge in Type I IFN is independent of the antigens encoded by each vaccine, we hypothesized that mRNA vaccines encoding non-tumor antigens, including those targeting SARS-COV-2, would similarly augment responses to ICI. To test this hypothesis, we tested replicas of the commercially available SARS-CoV-2 vaccines in ICI-resistant murine models of melanoma and non-small cell lung cancer. We then assessed correlates of response to SARS-CoV-2 mRNA vaccination in healthy volunteers (n=15) and three retrospective cohorts of patients with Stage III/IV non-small cell lung cancer (NSCLC) (n=2,406), metastatic melanoma (n=757), and a tissue-agnostic cohort (n=5,524) with biopsy specimens Aug 2021-Aug 2023. In preclinical models, Type I IFN stimulated by SARS-COV-2 mRNA vaccines drove systemic innate immune activation and expansion of tumor-reactive T cells, leading to increased expression of PD-L1 on tumor cells and inhibition of growth of established models of melanoma (B16F0) and non-small cell lung cancer (LLC). In humans, SARS-CoV-2 mRNA vaccines were associated with a surge in Type I IFN (Range 10-400 fold increase over baseline, p<0.001), increased PD-L1 expression on biopsy samples (17% vs 10%, p<0.001), and improved survival in metastatic NSCLC (median OS 1,120 vs. 555 days; HR 0.5, p<0.001) and melanoma (HR 0.42, 95% CI 0.24-0.74, p=0.003). Unexpectedly, SARS-CoV-2 mRNA vaccination led to a striking increase in PD-L1 expression on intracranial tumors (57% vs. 7.2%, p<0.001), and numerically improved survival among patients with melanoma brain metastases (n=48) (median 545 days vs unmet, HR 0.50, p=0.06). Together, this data suggests that mRNA vaccines induce secretion of Type I IFN that leads to enhanced PD-L1 expression and efficacy of ICIs. This effect is particularly notable in patients with intracranial metastases, suggesting potential therapeutic implications for this high-risk population.

Source: Neuro-Oncology

DOI: 10.1093/neuonc/noaf201.0887