Owing to high rates of tumor relapse, ovarian cancer remains a fatal disease for which new therapeutic approaches are urgently needed. Accumulating evidence indicates that immune stimulation may delay or even prevent disease recurrence in ovarian cancer. In order to elicit proinflammatory signals that induce or amplify antitumor immune reactivity, we mimicked viral infection in ascites-derived ovarian cancer cells. By transfection or electroporation we targeted the synthetic double-stranded RNA poly(I:C) intracellularly in order to activate melanoma differentiation-associated gene-5 (MDA-5), a sensor of viral RNA in the cytosol of somatic cells. Cancer cells reacted with enhanced expression of HLAclass I, release of CXCL10, IL-6, and type I IFN as well as tumor cell apoptosis. Monocytes and monocyte-derived DCs (MoDCs) engulfed MDA-5-activated cancer cells, and subsequently upregulated HLA-class I/II and costimulatory molecules, and secreted CXCL10 and IFN-a. Further, this proinflammatory milieu promoted cytolytic activity and IFN-c secretion of NK cells. Thus, our data suggest that the engagement of MDA-5 in a whole tumor cell vaccine is a promising approach for the immunotherapy of ovarian cancer.

A major strength of this current research is the nationwide nature of our data network, which allows quantification of the magnitude of the challenge facing the rheumatology community in the immediate post-Roe era. However, we acknowledge the limitations of assessing the magnitude of this potential issue by using the distribution of existing patients taking MTX prior to the overturning of Roe v. Wade in a single data network, which had small numbers of patients for some states. As more updated data on MTX use become available, a state-by-state comparison of longitudinal use of MTX can shed light on the actual impact of the ruling. The issue of accessing MTX can also affect patients who are trying to initiate MTX therapy. We would like to emphasize the importance of ongoing data collection, including case reporting via the advocacy channel of the American College of Rheumatology (ACR)

BackgroundSeveral health authorities recommend a third (booster) vaccination to protect patients with rheumatic and musculoskeletal diseases from severe COVID-19. Methotrexate has been shown to reduce the efficacy of the first and second dose of SARS-CoV-2 mRNA vaccines. So far, it remains unknown how concomitant methotrexate affects the efficacy of a COVID-19 booster vaccination.MethodsWe compared the humoral immune response to SARS-CoV-2 vaccination in 136 patients with rheumatoid arthritis (RA) treated with methotrexate and/or biological or targeted synthetic (b/tsDMARDs). IgG targeting the receptor binding domain (RBD) of SARS-CoV-2 spike protein was measured at a median of 52.5 (range 2–147) days after a third dose of the SARS-CoV-2 mRNA vaccines BNT162b2 or mRNA-1273.ResultsAnti-RBD IgG was significantly reduced in elderly patients receiving concomitant treatment with methotrexate as compared with elderly patients receiving monotherapy with b/tsDMARDs or methotrexate (64.8 (20.8, 600.3) binding antibody units per mL (BAU/mL) vs 1106.0 (526.3, 4965.2) BAU/mL vs 1743.8 (734.5, 6779.6) BAU/mL, median (IQR), p<0.001, Kruskal-Wallis test). In younger patients (< 64.5 years), concomitant methotrexate had no significant impact on the humoral immune response.ConclusionsConcomitant methotrexate increases the risk of an insufficient humoral immune response to SARS-CoV-2 vaccination in elderly patients with RA. Pausing methotrexate during the third vaccination period may be considered for this group of patients.

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