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

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.