Expression und Regulation von CD276/ B7-H3 auf Blasentumorlinien und somatischen Urothelzellen

Das Harnblasenkarzinom zählt zu den häufigsten Krebsarten weltweit. Fast alle Harnblasenkarzinome sind Urothelzellkarzinome. Etwa die Hälfte der Fälle in Deutschland gehören zur prognostisch schlechteren Gruppe der invasiven Harnblasenkarzinome. Diese Tumoren müssen aufgrund ihrer größeren Ausbreitung potenziell intensiver therapiert werden. Ein wichtiger Baustein einer solchen Therapie kann eine Immuntherapie sein. Aktuell stehen hier für das Urothelzellkarzinom vor allem PD-1-Inhibitoren zu Verfügung. Wie PD-1 gehört auch CD276 zur immunmodularischen B7-Familie. Zielsetzung dieser Arbeit war es, das Expressionsverhalten von CD276 sowie dessen Regulation auf Urothelkarzinomzellen und auf somatischen Urothelzellkulturen zu untersuchen und so dieses potenziell therapeutisch relevante Molekül auf Urothelzellen besser verstehen zu können. Es wurden Zellkulturversuche und Immunfluoreszenzfärbungen von Gewebeproben durchgeführt, um die Expression von CD276 sowohl auf Zellebene als auch im gesamten histologischen Kontext beurteilen zu können. Die grundsätzliche Expression von CD276 war in den untersuchten Zellen sehr heterogen. Ebenso zeigte sich ein variables Bild bei einem Vergleich der Expression auf Transkriptebene, Proteinebene und auf der Zelloberfläche. Unter verschiedenen Triggerfaktoren wie Hypoxie, LPS, PMA und Ionomycin, FSL-1 und Mycoplasmen zeigte sich keine Änderung der Expression von CD276 auf Tumorzelllinien und somatischen Urothelzellkulturen. Die Auswertung der Immunfluoreszenz war erschwert durch die uneinheitlichen Auswertungsstrategien bereits publizierter Untersuchungen anderer Arbeitsgruppen. In dieser Arbeit konnte kein Zusammenhang der Expression von CD276 mit dem Ausbreitungsstadium des Tumors oder seines Differenzierungsgrads gezeigt werden. Eine signifikant erhöhte Expression von CD276 zeigte sich dagegen in Proben eines Patienten, der einige Zeit zuvor eine BCG-Instillation erhalten hatte. Weitere Studien sind nötig, um die Ergebnisse zu überprüfen und die Expression von CD276 auf Urothelkarzinomzellen zu erforschen

Efficacy of COVID-19 Booster Vaccines in Patients with Hematologic Malignancies: Experiences in a Real-World Scenario.

BACKGROUND Two-dose COVID-19 vaccination often results in poor humoral response rates in patients with hematologic malignancies (HMs); yet responses to COVID-19 booster vaccines and the risk of COVID-19 infection post-booster are mostly uncertain. METHODS We included 200 outpatients with HMs and predominantly lymphoid neoplasms (96%, 191/200) in our academic center and reported on the humoral responses, which were assessed by measurement of anti-spike IgG antibodies in peripheral blood as early as 14 days after mRNA-based prime-boost vaccination, as well as factors hampering booster efficacy. Previous basic (double) immunization was applied according to the local recommendations with mRNA- and/or vector-based vaccines. We also report on post-booster COVID-19 breakthrough infections that emerged in the Omicron era and the prophylaxis strategies that were applied to poor and non-responders to booster vaccines. RESULTS A total of 55% (110/200) of the patients achieved seroconversion (i.e., anti-spike protein IgG antibody titer > 100 AU/mL assessed in median 48 days after prime-boost vaccination) after prime-boost vaccination. Multivariable analyses revealed age, lymphocytopenia, ongoing treatment and prior anti-CD20 B-cell depletion to be independent predictors for booster failure. With each month between anti-CD20-mediated B-cell depletion and booster vaccination, the probability of seroconversion increased by approximately 4% (p < 0.001) and serum-antibody titer (S-AbT) levels increased by 90 AU/mL (p = 0.011). Notably, obinutuzumab treatment was associated with an 85% lower probability for seroconversion after prime-boost vaccination compared to rituximab (p = 0.002). Of poor or non-responders to prime-boost vaccination, 41% (47/114) underwent a second booster and 73% (83/114) underwent passive immunization. COVID-19 breakthrough infections were observed in 15% (29/200) of patients after prime-boost vaccination with predominantly mild courses (93%). Next to seroconversion, passive immunization was associated with a significantly lower risk of COVID-19 breakthrough infections after booster, even in vaccine non-responders (all p < 0.05). In a small proportion of analyzed patients with myeloid neoplasms (9/200), the seroconversion rate was higher compared to those with lymphoid ones (78% vs. 54%, accordingly), while the incidence rate of COVID-19 breakthrough infections was similar (22% vs. 14%, respectively). Following the low frequency of myeloid neoplasms in this study, the results may not be automatically applied to a larger cohort. CONCLUSIONS Patients with HMs are at a high risk of COVID-19 booster vaccine failure; yet COVID-19 breakthrough infections after prime-boost vaccination are predominantly mild. Booster failure can likely be overcome by passive immunization, thereby providing immune protection against COVID-19 and attenuating the severity of COVID-19 courses. Further sophistication of clinical algorithms for preventing post-vaccination COVID-19 breakthrough infections is urgently needed

Clinical Post-SARS-CoV-2 Infection Scenarios in Vaccinated and Non-Vaccinated Cancer Patients in Three German Cancer Centers: A Retrospective Analysis.

COVID-19 vaccines have become an integral element in the protection of cancer patients against SARS-CoV-2. To date, there are no direct comparisons of the course of COVID-19 infection in cancer patients between the pre- and post-vaccine era. We analyzed SARS-CoV-2 infections and their impact on cancer in COVID-19 vaccinated and non-vaccinated patients from three German cancer centers. Overall, 133 patients with SARS-CoV-2 were enrolled in pre- and post-vaccine eras: 84 non-vaccinated and 49 vaccinated, respectively. A mild course of COVID-19 was documented more frequently in vaccinated patients (49% vs. 29%), while the frequency of severe and critical courses occurred in approximately one-half of the non-vaccinated patients (22% vs. 42%, p = 0.023). Particularly, patients with hematologic neoplasms benefited from vaccination in this context (p = 0.031). Admissions to intermediate- and intensive-care units and the necessity of non-invasive and invasive respiratory support were reduced by 71% and 50% among vaccinated patients, respectively. The median length of admission was 11 days for non-vaccinated and 5 days for vaccinated patients (p = 0.002). COVID-19 mortality was reduced by 83% in vaccinated patients (p = 0.046). Finally, the median time from SARS-CoV-2 infection to restarting cancer therapy was 12 and 26 days among vaccinated and non-vaccinated groups, respectively (p = 0.002). Although this study does not have enough power to perform multivariate analyses to account for confounders, it provides data on COVID-19 in non-vaccinated and vaccinated cancer patients and illustrates the potential benefits of COVID-19 vaccines for these patients