3051 - Systemic Immune Activation by SARS-CoV-2 mRNA Vaccines Sensitizes Tumors to Immune Checkpoint Blockade
Presenter(s)
A. Grippin1, S. A. Copling2, C. Marconi3, N. Li4, A. Kim5, E. Young4, J. Jafarnia5, N. Nariman5, H. Mendez-Gomez6, W. Jiang Jr1, E. Sayour6, and S. H. Lin1; 1Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 2UTHealth Houston McGovern Medical School, Houston, TX, 3University of Florida, Gainesville, FL, 4The University of Texas MD Anderson Cancer Center, Houston, TX, 5McGovern Medical School, Houston, TX, 6University of Florida, Department of Neurosurgery, Gainesville, FL
Purpose/Objective(s): 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.
Materials/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, increased expression of PD-L1 on tumor cells, and significantly inhibited growth of established B16F0 tumors in combination with ICI. This effect required Type I IFN signaling but was not achieved 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, suggesting the generation of tumor-reactive T cells in vaccinated patients.
Conclusion: SARS-COV-2 mRNA vaccines produce a cytokine cascade that sensitizes tumors to ICI.