IMMUNE CHECKPOINT BLOCKADE, LYMPHOMA, TUMOR VIRUS
With the broad success of immune check-point blockade therapy in a wide variety of cancers adverse events have been noted in a subset of patients. Along with the search for patient stratifications to predict therapeutic success of these treatments also biomarkers for these adverse events should be identified to tailor immune modulatory treatments for maximal benefit with minimal harm. Among these adverse events are reactivations of persistent viral and mycobacterial infections in a subset of patients. We will investigate the persistent and oncogenic Epstein Barr virus (EBV) which has been found to cause pathologies during PD-1 inhibition or genetic CTLA4 insufficiency to characterize the cellular and molecular mechanisms underlying the respective loss of immune control. We hypothesize that IL-10 producing PD-1 and CTLA4 positive regulatory CD4+ T cell populations are activated during immune check-point inhibition and compromise EBV specific, mainly CD8+ T cell mediated immune control. This hypothesis will be tested in a preclinical in vivo model of EBV infection in which we already observed loss of EBV specific immune control with elevated IL-10 production during antibody mediated PD-1 blockade, as well as in patients with primary immunodeficiencies due to CTLA4 loss-of-function mutation, some of whom develop EBV associated malignancies and for whom we have contributed to their initial description. The proposed studies might provide insights into predictors of pathogenic EBV reactivations during immune check-point blockade, new insights into PD-1 and CTLA4 biology on regulatory T cells and suggest therapeutic modalities to counteract the associated adverse events.
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Valery Volk, Sebastian J. Theobald, Simon Danisch, Sahamoddin Khailaie, Maja Kalbarczyk, Andreas Schneider, Julia Bialek-Waldmann, Nicole Krönke, Yun Deng, Britta Eiz-Vesper, Anna C. Dragon, Constantin V. Kaisenberg, Stefan Lienenklaus, Andre Bleich, James Keck, Michael Meyer-Hermann, Frank Klawonn, Wolfgang Hammerschmidt, Henri- Jacques Delecluse, Christian Münz, Friedrich Feuerhake and Renata Stripecke. PD-1 blockade aggravates EBV+ PTLD in humanized mice resulting in central nervous system involvement and CD4+ T cell dysregulations. Frontiers in Oncology (2021), 10:614876.
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